naphthoquinones and quinone

A sensitive and stable signal multiplied quinone-linked immunosorbent assay (Multi-QuLISA) was developed. In Multi-QuLISA, an oligomerized quinone linked to biotin, namely biotin-8mer-naphthoquinone (Bio8mer-NQ), is used as a signal-generating label. Bio8mer-NQ is formed from a dendrigraft poly-l-lysine generation 1 (DPLL G1), a controlled branched oligomer composed of eight lysine moieties with nine free amino groups as a backbone. One of the nine amino groups of DPLL G1 is attached to biotin moiety, while the other eight are attached to 1,2-naphthoquinone-4-sulfonate (NQS). Bio8mer-NQ labels a biotinylated detection antibody using avidin as a co-binder. Then, multi-quinones in Bio8mer-NQ undergo a redox cycle with dithiothreitol and luminol, generating strong chemiluminescence. Standard ELISA uses a label enzyme that suffers from vulnerability in different conditions and poor stability. Bio8mer-NQ showed better stability than the enzyme (biotin-HRP) under different drastic pH and temperature conditions, hydrolytic enzymes, etc. Furthermore, Bio8mer-NQ was used as both chemiluminescence and colorimetric label based on the redox cycle of quinone, and it had LODs of 1.5 and 6.5 nM, respectively. The method could detect biotinylated immunocomplex in an in-house designed immunoassay down to 0.2 nM, which is about 25 times more sensitive than biotin HRP. Eventually, Bio8mer-NQ was applied successfully in Multi-QuLISA for detecting β-casein with a sensitivity of 3.2 ng/mL, while the conventional ELISA had an LOD of 35 ng/mL. Overall, Bio8mer-NQ is a stable compound that could be used as an excellent replacement for the enzyme in immunoassay and can be used in both colorimetric and chemiluminescence assays with good sensitivity.

Topics: Biotin; Immunosorbents; Naphthoquinones; Polylysine

Since NQO1 is overexpressed in many cancer cells, it can be used as a biomarker for cancer diagnosis and targeted therapy. NQO1 substrates show potent anticancer activity through the redox cycle mediated by NQO1, while the NQO1 probes can monitor NQO1 levels in cancers. High sensitivity of probes is needed for diagnostic imaging in clinic. In this study, based on the analysis of NQO1 catalytic pocket, the naphthoquinone trigger group 13 rationally designed by expanding the aromatic plane of the benzoquinone trigger group 10 shows significantly increased sensitivity to NQO1. The sensitivity of the naphthoquinone trigger group-based probe A was eight times higher than that of benzoquinone trigger group-based probe B in vivo. Probe A was selectively and efficiently sensitive to NQO1 with good safety profile and plasma stability, enabling its combination with NQO1 substrates in vivo for NQO1-overexpressing cancer theranostics for the first time.

Topics: A549 Cells; Animals; Antineoplastic Agents; Benzoquinones; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Fluorescent Dyes; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasms, Experimental; Optical Imaging; Structure-Activity Relationship; Substrate Specificity; Theranostic Nanomedicine

We synthesized novel vitamin K derivatives by converting the naphthoquinone group to benzene derivatives and benzoquinone. We evaluated their neuronal differentiation activities to investigate the effect of the quinone moiety on this process. We observed that the 1,4-quinone as well as the side chain part play important roles in neuronal differentiation. We also performed QSAR analysis to predict the compounds which would have higher differentiation activity.

Topics: Animals; Benzene Derivatives; Benzoquinones; Cell Differentiation; Dose-Response Relationship, Drug; Mice; Molecular Structure; Naphthoquinones; Neurons; Quantitative Structure-Activity Relationship; Vitamin K

Shikonin derivatives are red naphthoquinone pigments produced by several boraginaceous plants, such as Lithospermum erythrorhizon. These compounds are biosynthesized from p-hydroxybenzoic acid and geranyl diphosphate. The coupling reaction that yields m-geranyl-p-hydroxybenzoic acid has been actively characterized, but little is known about later biosynthetic reactions. Although 3″-hydroxy-geranylhydroquinone produced from geranylhydroquinone by CYP76B74 has been regarded as an intermediate of shikonin derivatives, the next intermediate has not yet been identified. This study describes a novel alcohol dehydrogenase activity in L. erythrorhizon cell cultures. This enzyme was shown to oxidize the 3″-alcoholic group of (Z)-3″-hydroxy-geranylhydroquinone to an aldehyde moiety concomitant with the isomerization at the C2'-C3' double bond from the Z-form to the E-form. An enzyme oxidizing this substrate was not detected in other plant cell cultures, suggesting that this enzyme is specific to L. erythrorhizon. The reaction product, (E)-3″-oxo-geranylhydroquinone, was further converted to deoxyshikonofuran, another meroterpenoid metabolite produced in L. erythrorhizon cells. Although nonenzymatic cyclization occurred slowly, it was more efficient in the presence of crude enzymes of L. erythrorhizon cells. This activity was detected in both shikonin-producing and nonproducing cells, suggesting that the aldehyde intermediate at the biosynthetic branch point between naphthalene and benzo/hydroquinone ring formation likely constitutes a key common intermediate in the synthesis of shikonin and benzoquinone products, respectively.

Topics: Alcohol Dehydrogenase; Aldehydes; Benzoquinones; Lithospermum; Metabolic Networks and Pathways; Naphthoquinones; Terpenes

An efficient annulation involving pyrone addition to a quinone and Dieckmann condensation was developed for rapid assembly of a γ-naphthopyrone monomeric precursor to the bis-naphthoquinone natural product aurofusarin. Dimerization was achieved through Pd

Topics: Benzoquinones; Catalysis; Crystallography, X-Ray; Dimerization; Isomerism; Molecular Conformation; Naphthoquinones; Palladium

Sepantronium bromide (YM155) is a small molecule antitumor agent currently in phase II clinical trials. Although developed as survivin suppressor, YM155's primary mode of action has recently been found to be DNA damage. However, the mechanism of DNA damage by YM155 is still unknown. Knowing the mechanism of action of an anticancer drug is necessary to formulate a rational drug combination and select a cancer type for achieving maximum clinical efficacy. Using cell-based assays, we showed that YM155 causes extensive DNA cleavage and reactive oxygen species generation. DNA cleavage by YM155 was found to be inhibited by radical scavengers and desferal. The reducing agent DTT and the cellular reducing system xanthine/xanthine oxidase were found to reductively activate YM155 and cause DNA cleavage. Unlike quinones, DNA cleavage by YM155 occurs in the presence of catalase and under hypoxic conditions, indicating that hydrogen peroxide and oxygen are not necessary. Although YM155 is a quinone, it does not follow a typical quinone mechanism. Consistent with these observations, a mechanism has been proposed that suggests that YM155 can cause oxidative DNA cleavage upon 2-electron reductive activation.

Topics: Antineoplastic Agents; Benzoquinones; Cell Line, Tumor; Cell Proliferation; Deferoxamine; DNA Cleavage; DNA Damage; Free Radical Scavengers; Humans; Imidazoles; Naphthoquinones; Oxidation-Reduction; Oxygen; Reactive Oxygen Species

The compounds produced by a living organism are most commonly as medicinal agents and starting materials for the preparation of new semi-synthetic derivatives. One of the largest groups of natural compounds consists of products containing a 1,4-benzoquinone subunit. This fragment occurs in three enediyne antibiotics, dynemicin A, deoxydynemicin A, and uncilamicin, which exhibit high biological activity. A series of alkoxy derivatives containing 1,4-naphthoquinone, 5,8-quinolinedione, and 2-methyl-5,8-quinolinedione moieties was synthesized. Moreover, the 1,4-benzoquinone subunit was contacted with an enediyne fragment. All obtained compounds were characterized by spectroscopy and spectrometry methods. The resulting alkane, alkene, alkyne and enediyne derivatives were tested as antitumor agents. They showed high cytotoxic activity depending on the type of 1,4-benzoquinone subunit and the employed tumor cell lines. The synthesized derivatives fulfill the Lipinski Rule of Five and have low permeability through the blood-brain barrier.

Topics: Anthraquinones; Antineoplastic Agents, Phytogenic; Benzoquinones; Biological Products; Cell Line, Tumor; Cell Survival; Enediynes; Humans; Inhibitory Concentration 50; Naphthoquinones; Organ Specificity; Quinolines; Structure-Activity Relationship

The modification of DNA by adduct formation is a potential molecular initiating event of genotoxicity. A chemoassay was established to study adduct formation of electrophiles with deoxynucleosides. Liquid chromatography-mass spectrometry was used to determine the reactivity of the model electrophiles para-benzoquinone, hydroquinone, and 1,4-naphthoquinone with deoxynucleoside (deoxyadenosine (dA), deoxyguanosine (dG), deoxycytidine (dC) and thymidine (dT)) to detect formation of adducts via constant neutral loss scan of deoxyribose (116 Da), and to elucidate adduct structures using high resolution mass spectrometry. Of the four deoxynucleosides dG was most susceptible, followed by dC and para-benzoquinone was the most reactive electrophile. With this approach five dG and four dC adducts were detected, formed by Michael addition and subsequent condensation. Also oxidation occurred with reactive oxygen species (ROS). Three of the adducts formed by benzoquinone have not been reported before. This chemoassay combined with mass spectrometry offers a way (a) to screen a large number of chemicals for their genotoxic potential, (b) to determine novel adducts that may be searched for in in vitro and in vivo studies and thus (c) to better understand the reaction of electrophiles with nucleobases.

Topics: Benzoquinones; Chromatography, Liquid; Deoxyadenosines; Deoxycytidine; Deoxyguanosine; Deoxyribonucleosides; DNA; DNA Adducts; DNA Damage; Mutagens; Naphthoquinones; Oxidants; Tandem Mass Spectrometry; Thymidine

Cell division cycle (CDC) 25 proteins are key phosphatases regulating cell cycle transition and proliferation by regulating CDK/cyclin complexes. Overexpression of these enzymes is frequently observed in cancer and is related to aggressiveness, high-grade tumors and poor prognosis. Thus, targeting CDC25 by compounds, able to inhibit their activity, appears a good therapeutic approach. Here, we describe the synthesis of a new inhibitor (SV37) whose structure is based on both coumarin and quinone moieties. An analytical in vitro approach shows that this compound efficiently inhibits all three purified human CDC25 isoforms (IC50 1-9 µM) in a mixed-type mode. Moreover, SV37 inhibits growth of breast cancer cell lines. In MDA-MB-231 cells, reactive oxygen species generation is followed by pCDK accumulation, a mark of CDC25 dysfunction. Eventually, SV37 treatment leads to activation of apoptosis and DNA cleavage, underlining the potential of this new type of coumarin-quinone structure.

Topics: Apoptosis; Benzoquinones; Breast Neoplasms; cdc25 Phosphatases; Cell Line, Tumor; Cell Proliferation; Coumarins; Cyclin-Dependent Kinases; DNA Cleavage; Female; Humans; MCF-7 Cells; Naphthoquinones; Protein Isoforms; Reactive Oxygen Species; Viral Proteins

Medermycin and kalafungin, two antibacterial and antitumor antibiotics isolated from different streptomycetes, share an identical polyketide skeleton core. The present study reported the discovery of kalafungin in a medermycin-producing streptomycete strain for the first time. A mutant strain obtained through UV mutagenesis showed a 3-fold increase in the production of this antibiotic, compared to the wild type strain. Heterologous expression experiments suggested that its production was severely controlled by the gene cluster for medermycin biosynthesis. In all, these findings suggested that kalafungin and medermycin could be accumulated by the same streptomycete and share their biosynthetic pathway to some extent in this strain.

Topics: Anti-Bacterial Agents; Benzoquinones; Chromatography, High Pressure Liquid; Disk Diffusion Antimicrobial Tests; Magnetic Resonance Spectroscopy; Mass Spectrometry; Multigene Family; Mutagenesis; Naphthoquinones; Staphylococcus epidermidis; Streptomyces; Ultraviolet Rays

Bimolecular fluorescence-quenching reactions involving electron-transfer between electronically excited 5,10,15,20-tetraphenyl-21H,23H-porphine (TPP*) and 1,4-benzoquinone (BQ) or 1,4-naphthoquinone (NQ) were investigated using a set of alkane solvents that enabled the rapid reaction kinetics to be probed over a wide viscosity range, while minimizing changes in other relevant solvent parameters. Relative diffusion coefficients and reaction distances were recovered directly from analysis of fluorescence decay curves measured on a nanosecond time scale. The electron transfer from TPP* to BQ requires reactant contact, consistent with tightly associated exciplex formation in these nonpolar solvents. In contrast, electron transfer from TPP* to NQ displays a clear distance dependence, indicative of reaction via a much looser noncontact exciplex. This difference is attributed to the greater steric hindrance associated with contact between the TPP*/NQ pair. The diffusion coefficients recovered from fluorescence decay curve analysis are markedly smaller than the corresponding measured bulk relative diffusion coefficients. Classical hydrodynamics theory was found to provide a satisfactory resolution of this apparent discrepancy. The calculated hydrodynamic radii of TPP and NQ correlate very well with the van der Waals values. The hydrodynamic radius obtained for BQ is a factor of 6 times smaller than the van der Waals value, indicative of a possible tight cofacial geometry in the (TPP(+)/BQ(-))* exciplex. The present work demonstrates the utility of a straightforward methodology, based on widely available instrumentation and data analysis, that is broadly applicable for direct determination of kinetic parameter values for a wide variety of rapid bimolecular fluorescence quenching reactions in fluid solution.

Topics: Alkanes; Benzoquinones; Diffusion; Electron Transport; Hydrodynamics; Naphthoquinones; Photochemical Processes; Porphyrins; Quantum Theory; Solvents

The objective of this research was to simultaneously analyze protein adducts of quinonoid metabolites of naphthalene and endogenous estrogen in serum albumin (Alb) derived from healthy pregnant women in Taiwan and to explore the correlations among them. The isomeric forms of cysteinyl adducts of naphthoquinones, including 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ) as well as estrogen quinones, including estrogen-2,3-quinones (E2-2,3-Q) and estrogen-3,4-quinones (E2-3,4-Q), are characterized after adduct cleavage. Results showed that the median levels of cysteinyl adducts of 1,2-NPQ and 1,4-NPQ on serum albumin were 249-390 and 16.0-24.8 pmol g(-1), respectively. Logged levels of 1,2-NPQ-Alb were correlated with logged levels of 1,4-NPQ-Alb (correlation coefficient r = 0.551, P < 0.001). Cysteinyl adducts of E2-2,3-Q-1-S-Alb, E2-2,3-Q-4-S-Alb, and E2-3,4-Q-2-S-Alb were detected in all subjects with median levels at 275-435, 162-288, and 197-254 pmol g(-1), respectively. We also found a positive relationship between logged levels of E2-2,3-Q-4-S-Alb and those of E2-3,4-Q-2-S-Alb (r = 0.770, P < 0.001).We noticed that median levels of E2-2,3-Q-derived adducts (E2-2,3-Q-1-S-Alb plus E2-2,3-Q-4-S-Alb) in pregnant women were greater than those of E2-3,4-Q-2-S-Alb (∼2-3-fold). Taken together, this evidence lends further support to the theme that cumulative concentration of E2-3,4-Q is a significant predictor of the risk of breast cancer. Furthermore, we noticed that levels of 1,2-NPQ-Alb are positively associated with levels of E2-3,4-Q-2-S-Alb (r = 0.522, P < 0.001) and those of E2-2,3-Q-4-S-Alb (r = 0.484, P < 0.001). Overall, this evidence suggests that environmental exposure to polycyclic aromatic hydrocarbons may modulate estrogen homeostasis and enhance the production of reactive quinone species of endogenous estrogen in humans.

Topics: Adult; Benzoquinones; Biomarkers; Body Burden; Breast Neoplasms; Environmental Exposure; Estradiol; Female; Humans; Naphthalenes; Naphthoquinones; Polycyclic Aromatic Hydrocarbons; Pregnancy; Quinones; Serum Albumin; Taiwan

A new protocol for the synthesis of protected amino-1,4-benzoquinones by oxidation of the corresponding 2,5-dimethoxyaniline derivatives using PhI(OAc)(2) or PhI(OCOCF(3))(2) in water containing 2.5% methanol is reported. The process represents an improvement over previously reported methods, both in terms of yield and number of steps, and in the range of nitrogen protecting groups that it tolerates. A number of novel aminobenzoquinones were prepared and subsequently used as dienophiles in Diels-Alder reactions to form building blocks for the synthesis of the aminonaphthoquinone antibiotics such as salinisporamycin.

Topics: Anti-Bacterial Agents; Benzoquinones; Chemistry Techniques, Synthetic; Isomerism; Naphthoquinones; Oxidation-Reduction

Lactococcus lactis is a gram-positive, normally homolactic fermenter that is known to produce several kinds of membrane associated quinones, which are able to mediate electron transfer to extracellular electron acceptors such as Fe(3+), Cu(2+) and hexacyanoferrate. Here we show that this bacterium is also capable of performing extracellular electron transfer to anodes by utilizing at least two soluble redox mediators, as suggested by the two-step catalytic current developed. One of these two mediators was herein suggested to be 2-amino-3-dicarboxy-1,4-naphthoquinone (ACNQ), via evaluation of standard redox potential, ability of the bacterium to exploit the quinone when exogenously provided, as well as by high performance liquid chromatography coupled with UV spectrum analysis. During electricity generation, L. lactis slightly deviated from its normal homolactic metabolism by excreting acetate and pyruvate in stoichiometric amounts with respect to the electrical current. In this metabolism, the anode takes on the role of electron sink for acetogenic fermentation. The finding that L. lactis self-catalyses anodic electron transfer by excretion of redox mediators is remarkable as the mechanisms of extracellular electron transfer by pure cultures of gram-positive bacteria had previously never been elucidated.

Topics: Benzoquinones; Biocatalysis; Bioelectric Energy Sources; Electric Conductivity; Electricity; Electrochemistry; Electrodes; Fermentation; Glucose; Lactococcus lactis; Naphthoquinones; Oxidation-Reduction; Solubility

A series of plumbagin derivatives (4a-4k) containing an amino acid moiety were synthesized under mild esterification conditions in excellent yields (35%-80%) and screened for their antifeedant activities in tobacco caterpillar (Spodoptera litura) and castor semilooper (Achaea janata) using a no-choice laboratory bioassay. The parent compound plumbagin lacked significant activity, but the analogues were effective in reducing feeding by two insect species. The introduction of an N-acetyl-l-amino acid side chain to the Michael adduct of plumbagin at the third position of the quinone moiety significantly increased antifeedant activity. Several of the analogues were also toxic or caused developmental abnormalities following topical administration.

Topics: Animals; Benzoquinones; Eating; Insecticides; Larva; Moths; Naphthoquinones; Spodoptera; Structure-Activity Relationship; Superoxides

Cytotoxicity of quinones has been attributed to free radical generation and to arylation of cellular nucleophiles. For redox-cycling quinones, cell injury is associated with mitochondrial permeability transition, whereas arylating quinones directly depolarise the mitochondrial membrane and deplete ATP. Like mitochondrial electron transport, plasma membrane electron transport (PMET), plays a multifaceted role in cellular redox homeostasis but the effects of quinones on PMET are unknown. Here we investigate the effects of redox-cycling 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), arylating 1,4-benzoquinone (BQ) and mixed mechanism 2-methyl-1,4-naphthoquinone (MNQ) on PMET, viability and growth of P815 mouse mastocytoma cells.BQ and MNQ rapidly and extensively inhibited PMET as determined by WST-1 /mPMS reduction (IC50 3.5-5 microM at 30 min) whereas the effects of DMNQ were less pronounced. In contrast, MTT reduction (cytosolic NADH dehydrogenase activity over 30 min) was weakly inhibited by BQ (IC50 20 microM) but not by MNQ or DMNQ and cell viability was unaffected. Inhibition of WST-1/mPMS reduction by BQ and MNQ but not DMNQ was fully reversed by NAC. Treatment with DMNQ, MNQ and to a lesser extent BQ inhibited cell proliferation as determined by MTT reduction at 48 h. The effects of BQ and MNQ were reversed by NAC through covalent bonding to BQ and MNQ, but not DMNQ. These results show that arylating quinones are more potent inhibitors of PMET than pure redox-cycling quinones, but that redox-cycling quinones are more cytotoxic.

Topics: Animals; Benzoquinones; Cell Line, Tumor; Cell Membrane; Cell Survival; Electron Transport; Mice; Naphthoquinones; Oxidation-Reduction; Quinones; Vitamin K 3

The synthesis and tumor-inhibitory activity of a series of aminonaphthoquinone derivatives of diospyrin, which was isolated from Diospyros montana Roxb., are presented here for the first time. An aminoacetate derivative showed the maximum (approximately 93%) increase in life span in vivo against murine Ehrlich ascites carcinoma (EAC) at a dose of 1 mg kg(-1)day(-1) (ip; five doses), and the lowest IC50 (0.06 microM) in vitro. Further, the same analogue also exhibited considerable enhancement in antiproliferative activity when evaluated against human cell lines, viz. malignant skin melanoma and epidermoid laryngeal carcinoma (IC50=0.06 and 0.92 microM, respectively) in comparison to the natural precursor, diospyrin (IC50=0.82 and 3.58 microM, respectively). Moreover, diospyrin and all its derivatives were found to show significantly greater (approximately 17- to 1441-fold) cytotoxicity against the tumor cells as compared to normal human lymphocytes. All these quinonoids generated substantial amounts of reactive oxygen species in EAC cells, more or less commensurate to their respective IC50 values.

Topics: Animals; Antineoplastic Agents; Benzoquinones; Carcinoma, Ehrlich Tumor; Cell Line, Tumor; Cell Proliferation; Drug Design; Electrochemistry; Humans; Mice; Naphthoquinones; Neoplasms; Oxidation-Reduction; Reactive Oxygen Species

Dialkyl disulfide-linked naphthoquinone, (NQ-Cn-S)2, and anthraquinone, (AQ-Cn-S)2, derivatives with different spacer alkyl chains (Cn: n=2, 6, 12) were synthesized and these quinone derivatives were self-assembled on a gold electrode. The formation of self-assembled monolayers (SAMs) of these derivatives on a gold electrode was confirmed by infrared reflection-absorption spectroscopy (IR-RAS). Electron transfer between the derivatives and the gold electrode was studied by cyclic voltammetry. On the cyclic voltammogram a reversible redox reaction between quinone (Q) and hydroquinone (QH2) was clearly observed under an aqueous condition. The formal potentials for NQ and AQ derivatives were -0.48 and -0.58 V, respectively, that did not depend on the spacer length. The oxidation and reduction peak currents were strongly dependent on the spacer alkyl chain length. The redox behavior of quinone derivatives depended on the pH condition of the buffer solution. The pH dependence was in agreement with a theoretical value of E 1/2 (mV)=E'-59pH for 2H+/2e(-) process in the pH range 3-11. In the range higher than pH 11, the value was estimated with E 1/2 (mV)=E'-30pH , which may correspond to H+/2e(-) process. The tunneling barrier coefficients (beta) for NQ and AQ SAMs were determined to be 0.12 and 0.73 per methylene group (CH2), respectively. Comparison of the structures and the alkyl chain length of quinones derivatives on these electron transfers on the electrode is made.

Topics: Anthraquinones; Benzoquinones; Disulfides; Electrodes; Electron Transport; Gold; Hydrogen-Ion Concentration; Naphthoquinones; Protons

In this work we studied the reaction of four quinones, 1,4-benzoquinone (1,4-BQ), 2,5-dimethyl-1,4-benzoquinone (2,5-DM-1,4-BQ), tetrachloro-1,4-benzoquinone (TC-1,4-BQ) and 1,4-naphthoquinone (1,4-NQ) with jack bean urease in phosphate buffer, pH 7.8. The enzyme was allowed to react with different concentrations of the quinones during different incubation times in aerobic conditions. Upon incubation the samples had their residual activities assayed and their thiol content titrated. The titration carried out with use of 5,5'-di-thiobis(2-nitrobenzoic) acid was done to examine the involvement of urease thiol groups in the quinone-induced inhibition. The quinones under investigation showed two distinct patterns of behaviour, one by 1,4-BQ, 2,5-DM-1,4-BQ and TC-1,4-BQ, and the other by 1,4-NQ. The former consisted of a concentration-dependent inactivation of urease where the enzyme-inhibitor equilibrium was achieved in no longer than 10min, and of the residual activity of the enzyme being linearly correlated with the number of modified thiols in urease. We concluded that arylation of the thiols in urease by these quinones resulting in conformational changes in the enzyme molecule is responsible for the inhibition. The other pattern of behaviour observed for 1,4-NQ consisted of time- and concentration-dependent inactivation of urease with a nonlinear residual activity-modified thiols dependence. This suggests that in 1,4-NQ inhibition, in addition to the arylation of thiols, operative are other reactions, most likely oxidations of thiols provoked by 1,4-NQ-catalyzed redox cycling. In terms of the inhibitory strength, the quinones studied formed a series: 1,4-NQ approximately 2,5-DM-1,4-BQ<1,4-BQ

Topics: Benzoquinones; Chloranil; Cyclohexenes; Enzyme Activation; Molecular Structure; Naphthoquinones; Protein Conformation; Structure-Activity Relationship; Sulfhydryl Compounds; Time Factors; Urease

These studies were conducted to determine the discrepancies between the spectroscopic data of the isolated and synthetic samples of the marine natural product (+)-elisabethadione. Attempts at the re-isolation of (+)-elisabethadione from Pseudopterogorgia elisabethae were unsuccessful, but during these efforts, two related natural products of O-methylelisabethadione (8) and O-methyl-nor-elisabethadione (9) were discovered. The total syntheses of these new natural products were accomplished by using the combined C-H activation/Cope rearrangement as the key step and the previously synthesized elisabethadione was converted to O-methylelisabethadione. These studies confirmed that the synthetic sample of (+)-elisabthadione was assigned the correct structure. The considerable differences in the data between the synthetic and natural samples of (+)-elisabethadione lead to the conclusion that the structure of the natural material was either miss-assigned or the published spectral data were incorrect. During the course of these studies, questions arose about the assigned structure of another natural product, elisabethamine, which was proposed to be an aminohydroquinone. Attempts at the synthesis of this compound revealed that the aminohydroquinone structure was unstable in air as it was readily oxidized to the quinone.

Topics: 2-Naphthylamine; Animals; Benzoquinones; Biological Products; Hydroquinones; Marine Biology; Methylation; Molecular Structure; Naphthoquinones; Sea Urchins; Spectrum Analysis; Stereoisomerism

In the last years there have been increasing reports of adverse cutaneous reactions to temporary black henna tattoos. Black henna does not exist naturally, it is obtained from original henna after the addition of other compounds, among them paraphenylenediamine (PPD), that darken it and facilitate the process of tattoing. Paraphenylenediamine is an aromatic compound that presents cross reactions with other components that have a benzene ring in their molecular structure. Many of these products may be present in the daily life of any person.. We reviewed patients that have shown erythema, inflammation and/or vesiculation in a previously tattooed area. The patients have undergone a temporary tattoo in street stalls during the summer period (2004-2005). A total of five patients were included, there were four men and one woman with a mean age of 13 years (3-34) and a mean latency period of 9.4 days (5-14). Black ink and plastic stencils were used to perform the tattoo. None of the patients has had previous contact with hair dyes or tattoos and none of them referred a personal history of atopic dermatitis. Patch testing was carried out using the standard set of the Spanish Group for Research in Contact Dermatitis [GEIDC] (TRUE TEST, Pharmacia. Hillerod. Denmark), with readings at 48 and 96 hours.. Sensitization to PPD is confirmed in three patients, one of them was also sensitized to formaldehyde. Hypopigmented scars persist in three patients.. Black henna pseudotattoos are a source of sensitization to PPD with potential severe consequences in a medium to long term. Currently there is no specific legislation with respect to the practice of this type of tattoos in our country.

Topics: Adult; Benzoquinones; Biotransformation; Child; Child, Preschool; Dermatitis, Allergic Contact; Female; Humans; Hypopigmentation; Ink; Male; Naphthoquinones; Patch Tests; Phenylenediamines; Prodrugs; Tattooing

The photoreduction of 1,4-benzoquinone, 1,4-naphthoquinone, 9,10-anthraquinone (AQ) and several methylated or halogenated derivatives in argon-saturated acetonitrile-water mixtures by indole, N-acetyltryptophan and N-acetyltyrosine was studied by time-resolved UV-vis spectroscopy using 20 ns UV laser pulses. The quinone triplet state is quenched by the aromatic amino acids and the rate constants are (1-5)x10(9)M(-1)s(-1). The semiquinone radical anion Q.(-) is the major observable transient after electron transfer from amino acids to the quinone triplet state. Termination of Q.(-) and amino acid derived radicals takes place in the mus-ms range. The effects of structure and other specific properties of quinones and amino acids are discussed. The radicals are subjects of intercept with oxygen, whereby hydrogen peroxide is eventually formed. The quantum yield of oxygen uptake Phi(-O2) as a measure of formation of hydrogen peroxide increases with increasing amino acid concentration, approaching Phi(-O2) for AQ in air-saturated solution.

Topics: Amino Acids, Aromatic; Anthraquinones; Benzoquinones; Electron Transport; Free Radicals; Halogens; Hydrogen Peroxide; Indoles; Kinetics; Methylation; Naphthoquinones; Oxidation-Reduction; Oxygen; Quinones; Spectrum Analysis; Tryptophan; Tyrosine; Ultraviolet Rays

Two mechanisms have been proposed to explain quinone cytotoxicity: oxidative stress via the redox cycle and the arylation of intracellular nucleophiles. As the redox cycle is catalyzed by NADPH cytochrome P450 reductase, cytochrome P450 systems are expected to be related to the cytotoxicity induced by redox-cycling quinones. Thus, we investigated the relationship between cytochrome P450 systems and quinone toxicity for rat primary hepatocytes using an arylator, 1,4-benzoquinone (BQ), and a redox cycler, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). The hepatocyte toxicity of both BQ and DMNQ increased in a time- and dose-dependent manner. Pretreatment with cytochrome P450 inhibitors, such as SKF-525A (SKF), ketoconazole and 2-methy-1,2-di-3-pyridyl-1-propanone, enhanced the hepatocyte toxicity induced by DMNQ but did not affect BQ-induced hepatocyte toxicity. The production of superoxide anion and the levels of glutathione disulfide and thiobarbituric-acid-reactive substances were increased by treatment with DMNQ, and SKF pretreatment further enhanced their increases. In addition, NADPH oxidation in microsomes was increased by treatment with DMNQ and further augmented by pretreatment with SKF, and a NADPH cytochrome P450 reductase inhibitor, diphenyleneiodonium chloride completely suppressed NADPH oxidations increased by treatment with either DMNQ- or DMNQ + SKF. Pretreatment with antioxidants, such as alpha-tocopherol, reduced glutathione, N-acetyl cysteine or an iron ion chelator deferoxamine, totally suppressed DMNQ- and DMNQ + SKF-induced hepatocyte toxicity. These results indicate that the hepatocyte toxicity of redox-cycling quinones is enhanced under cytochrome P450 inhibition, and that this enhancement is caused by the potentiation of oxidative stress.

Topics: Animals; Antioxidants; Benzoquinones; Catecholamines; Cell Survival; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Glutathione Disulfide; Hepatocytes; Imidazolines; Iron Chelating Agents; Ketoconazole; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Metyrapone; Molecular Structure; NADP; Naphthoquinones; Oxidative Stress; Proadifen; Rats; Rats, Wistar; Superoxides; Thiobarbituric Acid Reactive Substances

Some representative quinones, viz. one naphthoquinone (plumbagin) and five anthraquinones (alizarin, purpurin, chrysazin, emodin, and anthrarufin), were subjected to electrocoagulation. It was found that the rate and extent of coagulation of these compounds appears to correlate with the number and relative position of their phenolic substituent groups, and that all of the coagulated quinones could be recovered. Attempts were then made to electrochemically isolate three quinones, namely plumbagin, morindone and erythrolaccin, from natural sources.

Topics: Anthraquinones; Benzoquinones; Electrocoagulation; Morinda; Naphthoquinones; Pigments, Biological; Plumbaginaceae; Quinones

The quinones 1,4-naphthoquinone (NQ), methyl-1,4-naphthoquinone (MNQ), trimethyl-1,4-benzoquinone (TMQ) and 2,3-dimethoxy-5-methyl-1,4-benzoquinone (UQ-0) enhance the rate of nitric oxide (NO) reduction by ascorbate in nitrogen-saturated phosphate buffer (pH 7.4). The observed rate constants for this reaction were determined to be 16+/-2,215+/-6,290+/-14 and 462+/-18 M-1 s-1, for MNQ, TMQ, NQ and UQ-0, respectively. These rate constants increase with an increase in quinone one-electron redox potential at neutral pH, E1(7). Since NO production is enhanced under hypoxia and under certain pathological conditions, the observations obtained in this work are very relevant to such conditions.

Topics: Ascorbic Acid; Benzoquinones; Naphthoquinones; Nitric Oxide; Nitrogen Oxides; Nitrous Oxide; Oxidation-Reduction

An overview of the synthesis of the fungal metabolites (+)-dermolactone, (-)- semixanthomegnin, (+)- and (-)-mellein, (-)-ochratoxin alpha, (-)-(1R,3S)-thysanone, the enantiopure ventiloquinones L, E and G, and 8-desmethyleleutherin from a common chiral intermediate, is presented. Further methodology leading potentially toward extended quinones such as (3S,3'S)-xylindein is also outlined.

Topics: Benzoquinones; Fungi; Isocoumarins; Models, Chemical; Molecular Structure; Naphthoquinones; Ochratoxins; Phenols; Polycyclic Compounds; Pyrans; Pyrones; Stereoisomerism

NAD(P)H/quinone acceptor oxidoreductase type 1 (QR1) protects cells from cytotoxic and neoplastic effects of quinones though two-electron reduction. Kinetic experiments, docking, and binding affinity calculations were performed on a series of structurally varied quinone substrates. A good correlation between calculated and measured binding affinities from kinetic determinations was obtained. The experimental and theoretical studies independently support a model in which quinones (with one to three fused aromatic rings) bind in the QR1 active site utilizing a pi-stacking interaction with the isoalloxazine ring of the FAD cofactor.

Topics: Animals; Anthraquinones; Benzoquinones; Binding Sites; Flavins; Humans; Kinetics; Models, Chemical; Models, Molecular; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Rats; Structure-Activity Relationship; Substrate Specificity; Thermodynamics; Tyrosine

The toxicity of four quinones, 2,3-dimethoxy-1,4-naphthoquinone (DMONQ), 2-methyl-1,4-naphthoquinone (MNQ), 1,4-naphthoquinone (NQ), and 1,4-benzoquinone (BQ), which redox cycle or arlyate in mammalian cells, was determined in isolated trout (Oncorhynchus mykiss) hepatocytes. More than 70% of cells died in 3 h when exposed to BQ or NQ; 50% died in 7 h when exposed to MNQ, with no mortality compared to controls after 7 h DMONQ exposure. A suite of biochemical parameters was assessed for ability to discriminate these reactivity pathways in fish. Rapid depletion of glutathione (GSH) with appearance of glutathione disulfide (GSSG) and increased dichlorofluoroscein fluorescence were used as indicators of redox cycling, noted with DMONQ, MNQ, and NQ. Depletion of GSH with no GSSG accumulation, and loss of free protein thiol (PrSH) groups (nonreducible) indicated direct arylation by BQ. All toxicants rapidly oxidized NADH, with changes in NADPH noted later (BQ, NQ, MNQ) or not at all (DMONQ). Biochemical measures including cellular energy status, cytotoxicity, and measures of reactive oxygen species, along with the key parameters of GSH and PrSH redox status, allowed differentiation of responses associated with lethality. Chemicals that arylate were more potent than redox cyclers. Toxic pathway discrimination is needed to group chemicals for potency predictions and identification of structural parameters associated with distinct types of reactive toxicity, a necessary step for development of mechanistically based quantitative structure-activity relationships (QSARs) to predict chemical toxic potential. The commonality of reactivity mechanisms between rodents and fish was also demonstrated, a step essential for species extrapolations.

Topics: Adenine; Animals; Benzoquinones; Cell Death; Female; Glutathione; Glutathione Disulfide; Hepatocytes; Male; Molecular Structure; Naphthoquinones; Oncorhynchus mykiss; Oxidation-Reduction; Oxygen; Pyridines; Quantitative Structure-Activity Relationship; Reactive Oxygen Species; Sulfhydryl Compounds; Vitamin K 3

Many aspects of the toxicity of xenobiotic compounds have been attributed to the consequences of covalent modification of specific proteins, but the nature and specificity of protein targets for classes of electrophilic toxins remain largely uncharacterized. For inhaled toxicants, the point of exposure or absorption lies with epithelial cells lining the pulmonary tree. In this study, abundant proteins in human bronchial epithelial cells that are arylated in vitro by two quinonoid compounds, 1,4-benzoquinone (BQ) and 1,4-naphthoquinone (NQ) have been detected using (14)C-labeled quinones and two-dimensional gel electrophoresis. These proteins were identified using matrix assisted laser desorption/ionization mass spectrometry for tryptic mass mapping followed by sequence database searching. Corroborative identification of protein targets was obtained from the apparent isoelectric points, molecular weights, and the use of antibody probes. There were subtle differences in the protein targets of BQ and NQ, but both associated with the following abundant proteins, nucleophosmin, galectin-1, probable protein disulfide isomerase, protein disulfide isomerase, 60 kDa heat shock protein, mitochondrial stress-70 protein, epithelial cell marker protein, and S100-type calcium binding protein A14. We further delineate the properties of these proteins that make them preferred targets and the evidence these adducts present for delivery of these quinones to subcellular compartments.

Topics: Adolescent; Adult; Amino Acid Sequence; Autoradiography; Benzoquinones; Bronchi; Cells, Cultured; Electrophoresis, Gel, Two-Dimensional; Epithelial Cells; Female; Humans; Male; Mass Spectrometry; Naphthoquinones; Oxidation-Reduction; Peptide Mapping; Proteins

The antifungal activity of 1,4-naphthoquinones, 1,2-naphthoquinones, 1,4-benzoquinones, and anthraquinones from our natural products collection was tested by direct bioautography to identify natural products with potential use in agricultural fungal pathogen control. Quinones demonstrated good to moderate antifungal activity against Colletotrichum spp. Colletotrichum fragariae was the most sensitive species to quinone-based chemistry, Colletotrichum gloeosporioides had intermediate sensitivity, while Colletotrichum acutatum was the species least sensitive to these compounds.

Topics: Anthraquinones; Benzoquinones; Colletotrichum; Fungicides, Industrial; Naphthoquinones; Quinones

Rat liver epithelial cells were exposed to three quinones with different properties: menadione (2-methyl-1,4-naphthoquinone, vitamin K3), an alkylating as well as redox-cycling quinone, the strongly alkylating p-benzoquinone (BQ), and the non-arylating redox-cycler, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). All three quinones induced the activation of extracellular signal-regulated kinase (ERK) 1 and ERK 2 via the activation of epidermal growth factor receptor (EGFR) and MAPK/ERK kinases (MEK) 1/2. ERK activation resulted in phosphorylation at Ser-279 and Ser-282 of the gap junctional protein, connexin-43, known to result in the loss of gap junctional intercellular communication. Another EGFR-dependent pathway was stimulated, leading to the activation of the antiapoptotic kinase Akt via phosphoinositide 3-kinase. The activation of EGFR-dependent signaling by these quinones was by different mechanisms: (i) menadione, but not BQ or DMNQ, inhibited a protein-tyrosine phosphatase regulating the EGFR, as concluded from an EGFR dephosphorylation assay; (ii) although menadione-induced activation of ERK was unimpaired by pretreatment of cells with N-acetyl cysteine, activation by BQ and DMNQ was prevented; (iii) cellular glutathione (GSH) levels were strongly depleted by BQ. The mere depletion of GSH by application of diethyl maleate EGFR-dependently activated ERK and Akt, thus mimicking BQ effects. GSH levels were only moderately decreased by menadione and not affected by DMNQ. In summary, EGFR-dependent signaling was mediated by protein-tyrosine phosphatase inactivation (menadione), GSH depletion (BQ), and redox-cycling (DMNQ), funneling into the same signaling pathway.

Topics: Animals; Benzoquinones; Blotting, Western; Cell Line; Connexin 43; Dose-Response Relationship, Drug; Epithelial Cells; ErbB Receptors; Gap Junctions; Glutathione; HeLa Cells; Humans; Immunohistochemistry; Indicators and Reagents; Liver; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Models, Biological; Naphthoquinones; Oxidation-Reduction; Phosphorylation; Precipitin Tests; Rats; Signal Transduction; Time Factors; Ultraviolet Rays; Vitamin K 3

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that are converted to cytotoxic and carcinogenic metabolites, quinones, by detoxifying enzyme systems in animals. PAH metabolites such as the quinones can form Michael adducts with biological macromolecules containing reactive nucleophiles, making detection of exposure to PAHs difficult using conventional techniques. A technique has been developed for detecting exposure to PAHs. Tetramethylammonium hydroxide (TMAH) thermochemolysis coupled with GC/MS is proposed as an assay method for PAH quinones that have formed Michael adducts with biological molecules. Three PAH quinones (1,4-naphthoquinone, 1,2-naphthoquinone, and 1,4-anthraquinone) and 1,4-benzoquinone were reacted with cysteine, and the TMAH thermochemolysis method was used to assay for both thiol and amine adduction between the quinones and the cysteine. Additional studies with 1,4-naphthoquinone adducts to glutathione and bovine serum albumin showed the same thiol and amine TMAH thermochemolysis products with larger peptides as was observed with cysteine adducts. The TMAH GC/MS method clearly shows great promise for detecting PAH quinones, produced by enzymatic conversion of PAHs in biological systems, that have been converted to respective Michael adducts.

Topics: Animals; Anthraquinones; Benzoquinones; Cattle; Cysteine; Evaluation Studies as Topic; France; Gas Chromatography-Mass Spectrometry; Glutathione; Molecular Structure; Naphthoquinones; Polycyclic Aromatic Hydrocarbons; Quaternary Ammonium Compounds; Serum Albumin, Bovine

Topics: Anthracenes; Anti-Bacterial Agents; Benzoquinones; Catalysis; Indoles; Magnetic Resonance Spectroscopy; Molecular Structure; Naphthoquinones

Topics: Benzoquinones; Crystallography, X-Ray; Indoles; Magnetic Resonance Spectroscopy; Molecular Conformation; Molecular Structure; Naphthoquinones

It can be expected that extracellular electron transfer to regenerate NAD+ changes the glucose metabolism of the homofermentative lactic acid bacteria. In this work, the glucose metabolism of Lactobacillusplantarum and Lactococcus lactis was examined in resting cells with 2-amino-3-carboxy-1,4-naphthoquinone (ACNQ) as the electron transfer mediator and ferricyanide (Fe(CN)6(3-)) as the extracellular electron acceptor. NADH in the cells was oxidized by ACNQ with the aid of diaphorase, and the reduced ACNQ was reoxidized with Fe(CN)6(3-). The extracellular electron transfer system promoted the generation of pyruvate, acetate, and acetoin from glucose, and restricted lactate production. Diaphorase activity increased when cultivation was aerobic, and this increased the concentrations of pyruvate, acetate, and acetoin relative to the concentration of lactate to increase in the presence of ACNQ and Fe(CN)6(3-)

Topics: Aerobiosis; Anaerobiosis; Benzoquinones; Biological Transport; Culture Media; Electron Transport; Extracellular Space; Glucose; Lactic Acid; Lactobacillus; Lactococcus lactis; NAD; Naphthoquinones; Oxidation-Reduction; Propionibacterium

The inhibitory activity of 34 natural products of various structural classes on hydroxyphenylpyruvate dioxygenase (HPPD), the target site for triketone herbicides, and the mode of interaction of selected natural products were investigated. Recombinant HPPD from arabidopsis is sensitive to several classes of natural compounds including, in decreasing order of sensitivity, triketones, benzoquinones, naphthoquinones and anthraquinones. The triketone natural products acted as competitive tight-binding inhibitors, whereas the benzoquinones and naphthoquinones did not appear to bind tightly to HPPD. While these natural products may not have optimal structural features required for in vivo herbicidal activity, the differences in their kinetic behavior suggest that novel classes of HPPD inhibitors may be developed based on their structural backbones.

Topics: 4-Hydroxyphenylpyruvate Dioxygenase; Anthraquinones; Arabidopsis; Benzoquinones; Biological Products; Herbicides; Naphthoquinones; Recombinant Proteins; Structure-Activity Relationship

Chloranil and 2,3-dichloro-1,4-naphthoquinone have been linked to different natural and unnatural amino acids via a vinylic spacer. Two routes were developed for the facile preparation of these novel modified amino acids: the direct method, which can only be applied to secondary amines, and the indirect method (transamination reaction), which can be applied to any amino acid or ester.

Topics: Amino Acids; Benzoquinones; Chloranil; Indicators and Reagents; Magnetic Resonance Spectroscopy; Models, Chemical; Naphthoquinones

Flash-induced redox changes of b-type and c-type cytochromes have been studied in chromatophores from the aerobic photosynthetic bacterium Roseobacter denitrificans under redox-controlled conditions. The flash-oxidized primary donor P+ of the reaction center (RC) is rapidly re-reduced by heme H1 (Em,7 = 290 mV), heme H2 (Em,7 = 240 mV) or low-potential hemes L1/L2 (Em,7 = 90 mV) of the RC-bound tetraheme, depending on their redox state before photoexcitation. By titrating the extent of flash-induced low-potential heme oxidation, a midpoint potential equal to -50 mV has been determined for the primary quinone acceptor QA. Only the photo-oxidized heme H2 is re-reduced in tens of milliseconds, in a reaction sensitive to inhibitors of the bc1 complex, leading to the concomitant oxidation of a cytochrome c spectrally distinct from the RC-bound hemes. This reaction involves cytochrome c551 in a diffusional process. Participation of the bc1 complex in a cyclic electron transfer chain has been demonstrated by detection of flash-induced reduction of cytochrome b561, stimulated by antimycin and inhibited by myxothiazol. Cytochrome b561, reduced upon flash excitation, is re-oxidized slowly even in the absence of antimycin. The rate of reduction of cytochrome b561 in the presence of antimycin increases upon lowering the ambient redox potential, most likely reflecting the progressive prereduction of the ubiquinone pool. Chromatophores contain approximately 20 ubiquinone-10 molecules per RC. At the optimal redox poise, approximately 0.3 cytochrome b molecules per RC are reduced following flash excitation. Cytochrome b reduction titrates out at Eh < 100 mV, when low-potential heme(s) rapidly re-reduce P+ preventing cyclic electron transfer. Results can be rationalized in the framework of a Q-cycle-type model.

Topics: Antimycin A; Bacteria; Bacterial Physiological Phenomena; Benzoquinones; Cytochrome b Group; Cytochrome c Group; Electron Transport Complex III; Electrons; Enzyme Inhibitors; Ferricyanides; Kinetics; Light; Methacrylates; Naphthoquinones; Oxidation-Reduction; Phenylenediamines; Photosynthesis; Photosynthetic Reaction Center Complex Proteins; Proteobacteria; Thiazoles; Time Factors; Titrimetry

Our previous studies demonstrated that menadione is cytotoxic to rat platelets. In an attempt to assess the relative contributions of enzymatic redox cycling versus arylation in menadione-induced cytotoxicity, we have studied three quinones with different mechanisms of action: 2,3-dimethoxy-1,4-naphthoquinone (DMNQ; pure redox cycler), menadione (both redox cycler and arylator), and 1,4-benzoquinone (BQ; pure arylator). BQ was more toxic to rat platelets than menadione, while DMNQ did not cause LDH leakage at all. Cellular uptake kinetics revealed that DMNQ concentration taken up by the cells was equivalent to that decreased in incubation medium. On the other hand, the concentrations of BQ and menadione taken into the cells were significantly lower than the decreases in concentrations seen in the incubation medium. This suggests indirectly that BQ and menadione may have undergone arylation, binding to glutathione (GSH) or protein thiols. The difference in arylation capacity between BQ and menadione was well correlated with their relative cytotoxicity (LDH leakage) observed in platelets. All three quinones caused a rapid, extensive depletion of intracellular GSH in platelets. Treatments with BQ and menadione did not result in formation of oxidized glutathione (GSSG), whereas DMNQ showed a time-dependent increase in GSSG. Altogether, these results suggest that enzymatic redox cycling does not play a critical role in quinone-induced cytotoxicity in rat platelets, while arylation is likely to be quinone's primary mechanism of action.

Topics: Alkylation; Animals; Benzoquinones; Blood Platelets; Cell Survival; Chromatography, High Pressure Liquid; Female; Glutathione; Homeostasis; L-Lactate Dehydrogenase; Naphthoquinones; Oxidative Stress; Oxygen Consumption; Quinones; Rats; Rats, Sprague-Dawley; Vitamin K

The mitochondrial permeability pore is subject to regulation by a thiol-dependent voltage sensor (Petronilli, V., Costantini, P., Scorrano, L., Colonna, R., Passamonti, S., and Bernardi, P., J. Biol. Chem. 269, 16638-16642, 1994); thiol oxidation increases the gating potential, which increases the probability of pore opening. Monofunctional sulfhydryl-alkylating agents, by preventing formation of the disulfide, inhibit oxidant-induced changes in the gating potential. According to this paradigm, redox-cycling and arylating quinones should have distinct and opposing effects on the voltage-dependent permeabilization of mitochondrial membranes. Freshly isolated rat liver mitochondria were susceptible to a calcium-dependent permeability transition characterized by osmotic swelling and membrane depolarization, both of which were inhibited by Cyclosporine A. 1,4-Naphthoquinone, 2-methyl-1,4-naphthoquinone (menadione), and 2,3-dimethoxy-1,4-naphthoquinone elicited an increase in gating potential of the permeability pore that was prevented by Cyclosporine A or N-ethylmaleimide and reversed by dithiothreitol. Benzoquinone, on the other hand, inhibited NADH-ubiquinone oxidoreductase. Accordingly, in mitochondria energized with glutamate plus malate benzoquinone caused a direct, calcium-independent depolarization of membrane potential and mitochondrial swelling that were not inhibited by Cyclosporine A. In contrast, benzoquinone did not interfere with succinate-supported mitochondrial bioenergetics. In fact, adding benzoquinone to succinate-energized mitochondria prevented induction of the mitochondrial permeability transition by all three redox-cycling naphthoquinones. We attribute this to the electrophilic, sulfhydryl-arylating reactivity of benzoquinone. The results suggest that differences in the mechanisms by which quinones of varying chemical reactivity interfere with mitochondrial bioenergetics can be explained in terms of the distinct manner in which they react with the thiol-dependent voltage sensor of the mitochondrial permeability pore.

Topics: Animals; Benzoquinones; Energy Metabolism; Glutamic Acid; In Vitro Techniques; Indicators and Reagents; Intracellular Membranes; Ion Channels; Malates; Membrane Potentials; Membrane Proteins; Mitochondria, Liver; Mitochondrial Swelling; Naphthoquinones; Oxidation-Reduction; Permeability; Porins; Rats; Voltage-Dependent Anion Channels

The antimicrobial activity of tobramycin against anaerobic cultures of Escherichia coli was tested in the presence of various electron carriers. The presence of 2,6-dichlorophenol 4-indophenol (DCIP) significantly enhanced the killing efficacy of tobramycin. Only 0.003% of the initial cell population (i.e. 10(6) cfu/mL) remained viable after exposure for 10 h to the mixture of antibiotic (20 x MIC, i.e. 40 mg/L) and electron acceptor (10(-3) M), as compared with 9% of surviving organisms in the presence of tobramycin alone. Less synergy was obtained with p-benzoquinone and 1,2-naphthoquinone. Fumarate did not affect the efficiency of the antibiotic. The mixture of tobramycin and DCIP was ineffective against agar-entrapped bacteria which, like biofilm organisms, are subject to oxygen limitation.

Topics: 2,6-Dichloroindophenol; Anaerobiosis; Anti-Bacterial Agents; Benzoquinones; Biofilms; Electrons; Escherichia coli; Fumarates; Indicators and Reagents; Microbial Sensitivity Tests; Naphthoquinones; Tobramycin

Menadione (2-methyl-1,4-naphthoquinone, a redox cycling and arylating quinone; 5-100 microM) inhibited the canalicular vacuolar accumulation (CVA) of a fluorescent bile acid, cholyl-lysyl-fluorescein (CLF), in rat hepatocyte couplets. This was associated with depletion of reduced glutathione and accumulation of oxidized glutathione, the latter indicating that the concentrations of menadione used were able to induce oxidative stress. There was no associated cytotoxicity as indicated by ATP content. Treatment of couplets with the redox cycling quinone 2,3-dimethoxy-1,4-naphthoquinone (up to 100 microM) had relatively little effect on CVA, suggesting that the magnitude of reactive oxygen formation induced by this compound was insufficient to disrupt canalicular integrity. In comparison, the arylation of protein thiol groups by p-benzoquinone (up to 100 microM) proved to be more potent in inhibiting canalicular vacuolar accumulation. The predominant mechanism of menadione-induced inhibition of couplet hepatobiliary function is therefore more likely to involve the arylation of critical thiol groups (such as those in the F-actin cytoskeleton) rather than their oxidation. The oxidative effects of menadione could, however, potentiate the deleterious effects induced by arylation, such as by reduced glutathione depletion.

Topics: Adenosine Triphosphate; Animals; Benzoquinones; Biliary Tract; Cell Membrane; Cell Separation; Glutathione; Homeostasis; Liver; Naphthoquinones; Oxidation-Reduction; Rats; Vacuoles; Vitamin K

Glutathione (GSH), an important physiological antioxidant, is synthesized de novo by the sequential reactions of gamma-glutamylcysteine synthetase (gamma GCS) and GSH synthetase. In the present studies, incubation with the quinones 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) and menadione (MQ), which generate superoxide and hydrogen peroxide, was used to investigate GSH synthesis in bovine pulmonary artery endothelial cells under oxidative stress. MQ can also cause initial depletion of GSH through conjugation, whereas DMNQ cannot. during continuous exposure to DMNQ (5 or 10 microM), elevation of GSH by DMNQ started after 6 h, almost doubled after 24 h, and remained at this level to 48 h. The elevation of GSH by DMNQ was mostly in the reduced form, and the ratio of reduced to oxidized glutathione remained unchanged for the first 24 h. Treatment with MQ (25 or 50 microM) for 30 min caused a significant decrease in GSH and total glutathione. After changing the medium to remove any residual MQ, GSH content doubled during the next 12 h. The enzymatic activity of gamma GCS, the rate-limiting enzyme of GSH biosynthesis, increased twofold after 12 h of exposure of cells to either 5 microM DMNQ or 50 microM MQ. Both DMNQ and MQ treatment caused concentration- and time-dependent increases in gamma GCS-mRNA expression. The elevation of gamma GCS-mRNA content by DMNQ for 12 h was completely blocked by coincubation with 0.05 microgram/ml actinomycin D but not 0.5 microgram/ml cycloheximide, suggesting the elevation of gamma GCS-mRNA content occurred through increased transcription. Our results suggest that increased de novo GSH synthesis, mediated by an elevation in gamma GCS, constitutes an adaptive response to oxidative stress.

Topics: Animals; Base Sequence; Benzoquinones; Cattle; Cells, Cultured; Cycloheximide; Dactinomycin; Endothelium, Vascular; Glutamate-Cysteine Ligase; Glutathione; Molecular Probes; Molecular Sequence Data; Naphthoquinones; Oxidative Stress; Pulmonary Artery; RNA, Messenger

Selected substituted 1,4-benzoquinones, 1,4-naphthoquinones, and 9,10-anthraquinones were investigated as possible replacement quinones in spinach photosystem I (PSI) preparations that had been depleted of endogenous phylloquinone by extraction with hexane/methanol. As a criterion for successful biochemical reconstitution, the restoration of electron transfer was determined by measuring P-430 turnover at room temperature from flash-induced absorbance transients. Restoration of complete electron transfer between A0- and P-430 (terminal iron-sulfur centers, FAFB) was demonstrated by using phylloquinone, 2-methyl-3-decyl-1,4-naphthoquinone, 2-methyl-3-(isoprenyl)2-1,4-naphthoquinone, and 2-methyl-3-(isoprenyl)4-1,4-naphthoquinone. All other quinones tested did not restore P-430 turnover but acted as electron acceptors and oxidized A0-. It is concluded that the specificity of the replacement quinone for interaction with the primary acceptor, A0-, is low but additional structural constraints are required for the quinone occupying the A1 site to donate to the iron-sulfur center, Fx. It is suggested that the 3-phytyl side chain of phylloquinone and the 3-alkyl tails of the three naphthoquinones that restored P-430 turnover may be required for interaction with a hydrophobic domain of the A1 site in the PSI core to promote electron transfer to Fx and then to FAFB.

Topics: Anthraquinones; Benzoquinones; Binding Sites; Electron Transport; Naphthoquinones; Oxidation-Reduction; Photosynthetic Reaction Center Complex Proteins; Photosystem I Protein Complex; Vitamin K 1

Rates of enzymatic single-electron reduction of some myotoxic quinones to semiquinone metabolites in an in vitro xanthine oxidase/hypoxanthine/catalase system varied widely. Naphthoquinones, especially juglone, were found to undergo rapid single-electron reduction. Benzoquinones and benzoquinoneimines, as well as phenanthrene-9,10-quinone, benzo[a]pyrene-3,6-quinone, and diethylstilbestrolquinone, were also actively reduced. The anthraquinones danthron, doxorubicin and emodin were poorly metabolized in this system. N-Acetylcysteine inhibited quinone-stimulated cytochrome C reduction at high concentrations. The results of this study are discussed with respect to cytotoxicity and mutagenicity of selected quinones.

Topics: 1-Propanol; Acetylcysteine; Anthraquinones; Benzoquinones; Cytochrome c Group; Ethanol; Naphthoquinones; Oxidation-Reduction; Quinones; Xanthine Oxidase

The effect of several structurally related 1,4-benzoquinones (BQ) and 1,4-naphthoquinones (NQ) on the activity of rat hepatic glutathione S-transferases (GST) was studied. For the 1,4-benzoquinones, the extent of inhibition increased with an increasing number of halogen substituents. Neither the type of halogen nor the position of chlorine-atoms was of major importance. Similarly, 2,3-dichloro-NQ demonstrated a considerably higher inhibitory activity than 5-hydroxy-NQ. 2-Methyl derivatives of NQ did not inhibit GST activity at all. The irreversible nature of the inhibition was shown both by the time-course of the inhibition as well as by the fact that removal of the inhibitor by ultrafiltration did not restore the enzymatic activity. Incubation of quinones and enzyme in the presence of the competitive inhibitor S-hexyl-glutathione, slowed the inhibition considerably, indicating an involvement of the active site. Isoenzyme 3-3 was found to be most sensitive towards the whole series of inhibitors, whereas the activity of isoenzyme 2-2 was least affected in all cases. The inhibition by quinones is probably mainly due to covalent modification of a specific cysteine residue in or near the active site. The differential sensitivities of individual isoenzymes indicates that this residue is more accessible and/or easier modified in isoenzyme 3-3 than in any of the other isoenzymes tested. The findings suggest that quinones form a class of compounds from which a selective in vivo inhibitor of the GST might be developed.

Topics: Animals; Benzoquinones; Glutathione; Glutathione Transferase; Isoenzymes; Liver; Molecular Structure; Naphthoquinones; Quinones; Rats; Structure-Activity Relationship

The nucleophilic addition of GSH to quinonoid compounds, characterized as a 1,4-reductive addition of the Michael type, was studied with p-benzoquinone- and 1,4-naphthoquinone epoxides with different degree of methyl substitution. Identification and evaluation of molecular products from the above reaction were assessed by h.p.l.c. with either reductive or oxidative electrochemical detection, based on the redox properties retained in the molecular products formed. It was found that the degree of methyl substitution of the quinone epoxide, from either the 1,4-naphthoquinone- or p-benzoquinone epoxide series, determined their rate of reaction with GSH. The reductive addition implied the rearrangement of the quinone structure with opening of the epoxide ring yielding as the primary product a hydroxy-glutathionyl substituted adduct of either p-benzohydroquinone or 1,4-naphthohydroquinone. The primary product undergoes elimination reactions and redox transitions which bring about a number of secondary molecular products. The distribution pattern of the latter depends on the degree of methyl substitution of the quinone epoxide studied and on the concentration of O2 in the solution. The occurrence of the hydroxy-substituent in position alpha, adjacent to the carbonyl group, enhances the autoxidation properties of the compound resulting in an augmented O2 consumption and H2O2 production. Therefore, it could be expected that the chemical reactivity of the products originating from the thiol-mediated nucleophilic addition to quinone epoxides would be of toxicological interest.

Topics: Benzoquinones; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Epoxy Compounds; Ethers, Cyclic; Free Radicals; Glutathione; Hydrogen Peroxide; Kinetics; Naphthoquinones; Oxidation-Reduction; Oxygen; Quinones; Vitamin K

Quinones may be toxic by a number of mechanisms, including oxidative stress caused by redox cycling and arylation. This study has compared the cytotoxicity of four quinones, with differing abilities to arylate cellular nucleophiles and redox cycle, in relation to their effects on cellular pyridine nucleotides and ATP levels in rat hepatocytes. Non-toxic concentrations (50 microM) of menadione (redox cycles and arylates), 2-hydroxy-1,4-naphthoquinone (neither arylates nor redox cycles via a one electron reduction) and 2,3-dimethoxy-1,4-naphthoquinone (a pure redox cycler) all caused markedly similar changes in cellular pyridine nucleotides. An initial decrease in NAD+ was accompanied by a small, transient increase in NADP+ and followed by a larger, prolonged increased in NADPH and total NADP+ + NADPH. At toxic concentrations (200 microM), the quinones caused an extensive depletion of NAD(H), an increase in levels of NADP+ and an initial rise in total NADP+ + NADPH, prior to a decrease in ATP levels and cell death. Nucleotide changes were not observed with non-toxic (20 microM) or toxic (100 microM) concentrations of p-benzoquinone (a pure arylator) and ATP loss accompanied or followed cell death. A novel mechanism for the activation of 2-hydroxy-1,4-naphthoquinone has been implicated. Our findings also suggest that a primary event in the response of the cell to redox cycling quinones is to bring about an interconversion of pyridine nucleotides, possibly mediated by an NAD+ reduction, in an attempt to combat the effects of oxidative stress.

Topics: Animals; Benzoquinones; Cell Survival; In Vitro Techniques; Liver; Male; NAD; NADP; Naphthoquinones; Oxidation-Reduction; Quinones; Rats; Rats, Inbred Strains; Vitamin K

1,4-Benzoquinone is cytotoxic in V79 Chinese hamster cells and induces gene mutations and micronuclei. The cell-damaging effects of quinones are usually attributed to thiol depletion, oxidation of NAD(P)H, and redox-cycling involving the formation of semiquinone radicals and reactive oxygen species. To elucidate the role of these mechanisms in the genotoxicity of 1,4-benzoquinone, we measured various genotoxic effects, cytotoxicity, and the levels of glutathione, NADPH, NADH, and their oxidized forms all in the same experiment. 1,4-Naphthoquinone, which does not induce gene mutations in V79 cells, was investigated for comparative reasons. The quinones had a similar effect on the levels of cofactors. Total glutathione was depleted, but levels of oxidized glutathione were slightly increased. The levels of NADPH and NADH were reduced at high concentrations of the quinones with a simultaneous increase in the levels of NADP+ and NAD+. Both compounds induced micronuclei, but neither increased the frequency of sister chromatid exchange. Only 1,4-benzoquinone induced gene mutations. This effect was observed at low concentrations, where none of the other parameters studied was affected. When the cells were depleted of glutathione prior to treatment with the quinones, the induction of gene mutations and micronuclei remained virtually unchanged. We conclude that a) induction of micronuclei and glutathione depletion by the two quinones are not linked causally, b) 1,4-benzoquinone induces gene mutations by a mechanism different from oxidative stress and glutathione depletion, and c) glutathione does not fully protect the cells against the genotoxicity of quinones.

Topics: Animals; Benzoquinones; Cell Line; Cell Survival; Glutathione; Mutagenicity Tests; Mutagens; NAD; NADP; Naphthoquinones; Oxidation-Reduction; Quinones

The oxidation of various quinones by H2O2 results in quinone epoxide formation. The yield of epoxidation is inversely related to the degree of methyl substitution of the quinone and seems not to be dependent on the redox potential of the quinones studied. The following order of H2O2-mediated epoxidation of quinones was found: p-benzoquinone greater than or equal to 1,4-naphthoquinone greater than 2-methyl-p-benzoquinone greater than 2,6-dimethyl-p-benzoquinone greater than or equal to 2-methyl-1,4-naphthoquinone greater than 2,3-dimethyl-1,4-naphthoquinone. DT-Diaphorase reduces several quinone epoxides at different rates. The rate of quinone epoxide reduction cannot be related to either the redox potential of the quinone epoxide (as reflected by the half-wave potential calculated from the corresponding hydrodynamic voltamograms) or the degree of substitution of the quinone epoxide. It appears, however, that a quinone epoxide redox potential more negative than -0.5 to -0.6 volts settles a threshold for the electron transfer reaction. This does not exclude that specificity requirements, i.e. the formation of the quinone epoxide substrate-enzyme complex may chiefly determine the rate of reduction of quinone epoxides by DT-diaphorase. DT-diaphorase-catalyzed two-electron transfer to quinone epoxides--resulting in epoxide ring opening--yields 2-OH-p-benzohydroquinone or 2-OH-1,4-naphthohydroquinone products. These hydroxy-derivatives show a higher rate of autoxidation than do the parent hydroquinones lacking the OH substituent.

Topics: Benzoquinones; Electrons; Epoxy Compounds; Hydrogen Peroxide; Kinetics; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Oxidation-Reduction; Quinone Reductases; Quinones; Substrate Specificity

Several quinoid compounds mediated the reduction of ferrylmyoglobin (MbIV) to metmyoglobin (MbIII). The efficiency of the MbIV reduction to MbIII was accomplished by the quinones in the following order: p-benzoquinone greater than 1,4-naphthoquinone greater than 2-OH-1,4-naphthoquinone greater than 2,3-epoxy-1,4-naphthoquinone. The quinone-mediated reduction of MbIV to MbIII had the following characteristics: (a) it was stoichiometrically--rather than catalytically--related to the number of cycles of the MbIV----MbIII transition involving the reduction of H2O2. (b) It proceeded with similar efficiencies under aerobic and anaerobic conditions. (c) It did not require the free radical form of MbIV(.MbIV), thus excluding a two-electron oxidation of the quinone. (d) the nucleophilic addition of--NH2 groups of the apoprotein on the quinone seemed not to be involved through an alternative pathway in the reduction of MbIV, especially since 2-OH-1,4-naphthoquinone, a compound which cannot undergo nucleophilic addition, also facilitated the reduction of the ferryl compound. (e) No two-electron oxidation products of the unsubstituted quinones, such as quinone epoxides, were detected in the spent reaction mixture analyzed by HPLC with electrochemical detection. On the basis of these observations, it is suggested that the reduction of MbIV to MbIII by the above quinonoid compounds is a one-electron transfer process, with electron abstraction being probably accomplished at some site in the benzo ring of the quinone.

Topics: Benzoquinones; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Hemeproteins; Hydrogen Peroxide; Kinetics; Metmyoglobin; Naphthoquinones; Oxidation-Reduction; Quinones; Spectrophotometry

Phenol and 1-naphthol, products of benzene and naphthalene biotransformation, are metabolized during O2- generation by xanthine oxidase/hypoxanthine and phorbol myristate acetate (PMA)-stimulated human neutrophils. The addition of 1-naphthol to xanthine oxidase/hypoxanthine incubations resulted in the formation of 1,4-naphthoquinone (1,4-NQ) whereas phenol addition yielded only small quantities of hydroquinone, catechol and a unidentified reducible product but not 1,4-benzoquinone. This formation of 1,4-NQ was dependent upon hypoxanthine, xanthine oxidase, and 1-naphthol and was inhibited by the addition of superoxide dismutase (SOD) demonstrating that the conversion was O2-mediated. During O2- generation by PMA-stimulated neutrophils, the addition of phenol interfered with luminol-dependent chemiluminescence and resulted in covalent binding of phenol to protein. Protein binding was 80% inhibited by the addition of azide or catalase to the incubations indicating that bioactivation was peroxidase-mediated. In contrast, the addition of 1-naphthol to PMA-stimulated neutrophils interfered with superoxide-dependent cytochrome c reduction as well as luminol-dependent chemiluminescence and also resulted in protein binding. Protein binding was only partially inhibited by azide or catalase. The addition of SOD in combination with catalase resulted in a significantly greater inhibition of binding when compared to that of catalase alone. The results of these experiments indicate that phenol and 1-naphthol are converted to reactive metabolites during superoxide generating conditions but by different mechanisms. The formation of reactive metabolites from phenol was almost exclusively peroxidase-mediated whereas the bioactivation of 1-naphthol could occur by two different mechanisms, a peroxidase-dependent and a direct superoxide-dependent mechanism.

Topics: Benzoquinones; Biotransformation; Blood Proteins; Chromatography, High Pressure Liquid; Humans; Hypoxanthine; Hypoxanthines; Luminescent Measurements; Naphthols; Naphthoquinones; Neutrophils; Phenol; Phenols; Quinones; Superoxide Dismutase; Superoxides; Tetradecanoylphorbol Acetate; Xanthine Oxidase

Using ESR spectroscopy, we show that benzoquinone, 1,4-naphthoquinone and 5-hydroxy-1,4-naphthoquinone react readily with thiol containing compounds, such as glutathione, to form their respective semiquinone anion radicals. These quinones react similarly, but less readily, with the amino group of amino acids. The therapeutic or toxicological significance of the formation of semiquinone anion radicals from the reaction of quinones with nucleophiles, such as thiols and amines, remains to be assessed.

Topics: Amino Acids; Benzoquinones; Chemical Phenomena; Chemistry; Electron Spin Resonance Spectroscopy; Glutathione; Naphthoquinones; Quinones

In reaction centers from Rhodobacter sphaeroides (formerly called Rhodopseudomonas sphaeroides), light causes an electron-transfer reaction that forms the radical pair state (P+I-, or PF) from the initial excited singlet state (P) of a bacteriochlorophyll dimer (P). Subsequent electron transfer to a quinone (Q) produces the state P+Q-. Back electron transfer can regenerate P from P+Q-, giving rise to 'delayed' fluorescence that decays with approximately the same lifetime as P+Q-. The free-energy difference between P+Q- and P can be determined from the initial amplitude of the delayed fluorescence. In the present work, we extracted the native quinone (ubiquinone) from Rps. sphaeroides reaction centers, and replaced it by various anthraquinones, naphthoquinones, and benzoquinones. We found a rough correlation between the halfwave reduction potential (E1/2) of the quinone used for reconstitution (as measured polarographically in dimethylformamide) and the apparent free energy of the state P+Q- relatively to P. As the E1/2 of the quinone becomes more negative, the standard free-energy gap between P+Q- and P decreases. However, the correlation is quantitatively weak. Apparently, the effective midpoint potentials (Em) of the quinones in situ depend subtly on interactions with the protein environment in the reaction center. Using the value of the Em for ubiquinone determined in native reaction centers as a reference, and the standard free energies determined for P+Q- in reaction centers reconstituted with other quinones, the effective Em values of 12 different quinones in situ are estimated. In native reaction centers, or in reaction centers reconstituted with quinones that give a standard free-energy gap of more than about 0.8 eV between P+Q- and P*, charge recombination from P+Q- to the ground state (PQ) occurs almost exclusively by a temperature-insensitive mechanism, presumably electron tunneling. When reaction centers are reconstituted with quinones that give a free-energy gap between P+Q- and P* of less than 0.8 with quinones that give a free-energy gap between P+Q- and P* of less than 0.8 eV, part or all of the decay proceeds through a thermally accessible intermediate. There is a linear relationship between the log of the rate constant for the decay of P+Q- via the intermediate state and the standard free energy of P+Q-. The higher the free energy, the faster the decay. The kinetic and thermodynamic properties of the intermediate appear not to depend str

Topics: Anthraquinones; Bacterial Proteins; Benzoquinones; Electron Transport; Energy Transfer; Kinetics; Light-Harvesting Protein Complexes; Mathematics; Models, Chemical; Naphthoquinones; Photosynthetic Reaction Center Complex Proteins; Quinones; Rhodopseudomonas; Ubiquinone

Doxorubicin is an anthracycline antibiotic with a very wide spectrum of anticancer activity. It has a great potential for clinical cardiotoxicity, however. One mechanism suggested for the cardiotoxicity is inhibition of ubiquinone-dependent enzymes. It was our purpose to study this possible mechanism using ubiquinone antagonists as probes. The effect on doxorubicin toxicity of three in vitro ubiquinone antagonists was tested in mice. Two of the antagonists, 2-hydroxy-3-n-dodecylmercapto-1,4-naphthoquinone and 2,3-dimethoxy-5-beta-naphthylmercapto-1,4-benzoquinone, enhanced doxorubicin toxicity in vivo as measured by survival. The latter was significantly toxic to mice, by itself. This effect was completely blocked by ubiquinone pretreatment, but only reduced by tocopherol pretreatment. Neither ubiquinone nor tocopherol was able to decrease the toxic interaction between doxorubicin and either of the ubiquinone antagonists. Cardiac and hepatic glutathione reductase and glutathione peroxidase activities were measured in studies using the 2,3-dimethoxy-5-beta-naphthylmercapto-1,4-benzoquinone. This compound appeared to cause a slight reduction in the activity of hepatic glutathione reductase. It appears that these antagonists are not useful to probe the relationship between doxorubicin cardiotoxicity and ubiquinone enzyme inhibition.

Topics: Animals; Benzoquinones; Doxorubicin; Female; Glutathione Peroxidase; Glutathione Reductase; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Naphthoquinones; Quinones; Ubiquinone; Vitamin E

The mutagenicities of naturally occurring naphthoquinones and benzoquinones were tested by the pre-incubation method with Salmonella typhimurium strains TA98, TA100 and TA2637, which all contain plasmid pKM101. 6 of the 16 naphthoquinones tested, i.e., plumbagin, naphthazarin, 2-hydroxy-naphthoquinone, vitamin K3 (menadione), juglone and 7-methyljuglone, were mutagenic to strain TA2637 with metabolic activation. Except for juglone and 7-methyl-juglone, these compounds also had slight mutagenic effects on strain TA98 with S9 mix. All the mutagenic naphthoquinones contain one or two hydroxyl and/or methyl substituents. The naphthoquinone mompain, which has four hydroxyl groups, was not mutagenic. Unsubstituted beta-naphthoquinone, naphthoquinones with a prenyl side chain and all bi-naphthoquinone derivatives tested were non-mutagenic. None of the 13 benzoquinones examined was mutagenic to any of the strains used with or without metabolic activation. These results show that natural naphthoquinones are mutagenic when they have only one or two hydroxyl and/or methyl substituents.

Topics: Animals; Benzoquinones; Biotransformation; Microsomes, Liver; Mutagenicity Tests; Mutagens; Mutation; Naphthoquinones; Plasmids; Quinones; Rats; Salmonella typhimurium; Structure-Activity Relationship

The in vitro interaction of 1,4-benzoquinone, 1,2- and 1,4-naphthoquinone, and 2-methyl-1,4-naphthoquinone with rat liver glutathione S-transferases (GST) was studied, using reduced glutathione and 1-chloro-2,4-dinitrobenzene (CDNB) as substrates. The inhibition of the GST activity by quinones in crude extracts was dose dependent. While most of the dihydroxynaphtalenes investigated also inhibited the GST activity, dihydroxybenzenes and catecholamines did not. The quinones inhibited all the GST isoenzymes, albeit at different degrees. Kinetic studies revealed mixed type function inhibition towards glutathione and competitive inhibition towards CDNB, implicating that quinones are GST substrates. This was further confirmed by titration of remaining glutathione in appropriate incubation mixtures. These results indicate that GST could have a protective function against quinones, and that catecholamines are conjugated with glutathione via a reactive quinone intermediate.

Topics: Animals; Benzoquinones; Glutathione Transferase; In Vitro Techniques; Isoenzymes; Kinetics; Liver; Male; Naphthoquinones; Quinones; Rats; Rats, Inbred Strains

Topics: Antifibrinolytic Agents; Benzoquinones; Blood Coagulation; Chemical Phenomena; Chemistry; Naphthoquinones; Pharmacology; Quinones; Rabbits; Research; Vitamin K

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Benzoquinones; Carcinoma, Ehrlich Tumor; Leukocyte Count; Mechlorethamine; Mice; Naphthoquinones; Quinones; Research; Thiotepa; Toxicology

Topics: Antifibrinolytic Agents; Benzoquinones; Blood Coagulation; Humans; Naphthoquinones; Quinones; Ubiquinone; Vitamin K

Topics: Animals; Benzoquinones; Cell Division; Chickens; Fibroblasts; Humans; Mitosis; Naphthoquinones; Quinones

Topics: Acetic Acid; Benzoquinones; Naphthoquinones; Polarography; Quinones; Radiation, Nonionizing; Vibration

Topics: Animals; Benzoquinones; Humans; Naphthoquinones; Neoplasms, Experimental; Quinones