curcumin and curcumin-glucuronide

Topics: Administration, Oral; Animals; Curcumin; Drug Evaluation, Preclinical; Estradiol; Glucuronides; Hepatocytes; Male; Mice; Mice, Knockout; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins

The diphenol curcumin from turmeric is rapidly metabolized into phase II conjugates following oral administration, resulting in negligible plasma concentration of the free compound, which is considered the bioactive form. Total plasma concentration of curcumin is often quantified after treatment with β-glucuronidase to hydrolyze curcumin-glucuronide, the most abundant conjugate in vivo. The efficiency of enzymatic hydrolysis has not been tested.. Using liquid chromatography-mass spectrometry (LC-MS) analyses the efficiency of β-glucuronidase and sulfatase from Helix pomatia is compared to hydrolyze curcumin conjugates in human and mouse plasma after oral administration of turmeric. Both β-glucuronidase and sulfatase completely hydrolyze curcumin-glucuronide. Unexpectedly, β-glucuronidase hydrolysis is incomplete, affording a large amount of curcumin-sulfate, whereas sulfatase hydrolyzed both glucuronide and sulfate conjugates. With sulfatase, the concentration of free curcumin is doubled in human and increased in mouse plasma compared to β-glucuronidase treatment. Incomplete hydrolysis by β-glucuronidase suggests the presence of mixed glucuronide-sulfate conjugates. LC-MS based searches detect diglucuronide, disulfate, and mixed sulfate-glucuronide and sulfate-diglucuronide conjugates in plasma that likely contribute to the increase of free curcumin upon sulfatase treatment.. β-Glucuronidase incompletely hydrolyzes complex sulfate-containing conjugates that appear to be major metabolites, resulting in an underestimation of the total plasma concentration of curcumin.

Topics: Adult; Animals; Curcumin; Female; Glucuronidase; Glucuronides; Humans; Hydrolysis; Male; Mice, Inbred C57BL; Middle Aged

Curcumin (CUR) is a major component of turmeric Curcuma longa, which is often used in food or as a dietary supplement. The purpose of this preclinical study is to investigate the acute pharmacokinetic and pharmacodynamic (PK/PD) profiles of two commercially marketed CUR products (GNC and Vitamin Shoppe) and a CUR powder from Sigma in female rats. Plasma samples were collected at specific time points and analyzed for CUR and its metabolite curcumin-O-glucuronide. RNA was extracted from leukocytes and analyzed for the expression of Nrf2-mediated antioxidant genes Nrf2, Ho-1, and Nqo1 by qPCR as selected PD markers. CUR PK was characterized by a 2-compartment model (2CM) after intravenous (IV) or oral administrations. Compared to IV CUR, the absolute bioavailability (F) of CUR for GNC (GC) is 0.9%, Vitamin Shoppe (VC) is 0.6% and Sigma (SC) is 3.1%. Pharmacodynamically, all three formulations showed induction of antioxidant Nrf2, Ho-1 and Nqo1 gene expression in rat leucocytes. PK/PD modeling of CUR's effect on antioxidant gene expression was well captured by an indirect response model. Physiologically based PK modeling and simulation using GastroPlus described the observed PK data reasonably well. In summary, our current study shows that the absolute oral bioavailability of the parent CUR was very low for all three formulations. However, despite the low CUR plasma concentrations, all three oral CUR formulations displayed PD response in the induction of Nrf2-mediated antioxidant genes, suggesting the potential of oral CUR contributing to the overall health beneficial effects of oral CUR.

Topics: Administration, Intravenous; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Curcuma; Curcumin; Drug Compounding; Female; Glucuronides; Heme Oxygenase-1; Leukocytes; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Plant Extracts; Powders; Rats; Rats, Sprague-Dawley; RNA, Messenger

Topics: Animals; Antineoplastic Agents; Colonic Neoplasms; Curcumin; Drug Resistance, Neoplasm; Female; Glucuronidase; Glucuronides; HCT116 Cells; Humans; Mice; Mice, Nude; Mutation; NF-kappa B; Oxaliplatin; Prodrugs; Proto-Oncogene Proteins p21(ras); Signal Transduction; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Curcumin prevents bone loss in resorptive bone diseases and inhibits osteoclast formation, a key process driving bone loss. Curcumin circulates as an inactive glucuronide that can be deconjugated in situ by bone's high β-glucuronidase (GUSB) content, forming the active aglycone. Because curcumin is a common remedy for musculoskeletal disease, effects of microenvironmental changes consequent to skeletal development or disease on bone curcumin metabolism are explored.. Across sexual/skeletal development or between sexes in C57BL/6 mice ingesting curcumin (500 mg kg. Dietary polyphenols circulating as glucuronides may require in situ deconjugation for bone-protective effects, a process influenced by bone microenvironmental changes.

Topics: Aging; Animals; Bone and Bones; Bone Neoplasms; Curcumin; Female; Glucuronidase; Glucuronides; Male; Mice, Inbred C57BL; Osteogenesis; Osteolysis; Osteoporosis; Ovariectomy; Polyphenols; Quercetin

This study aimed to investigate the potential pharmacokinetic interactions between curcumin, imatinib and bosutinib, combining In Vitro and in silico methods.. In Vitro metabolism of imatinib and bosutinib were investigated in pooled human liver microsomes and recombinant CYP3A4 enzyme in the presence and absence of curcumin and curcumin glucuronide using an LC-MS/MS assay for N-desmethyl metabolites. A physiologically-based pharmacokinetic (PBPK) model for curcumin formulated as solid lipid nanoparticles (SLN) was constructed using In Vitro glucuronidation kinetics and published clinical pharmacokinetic data. The potential effects of curcumin coadministration on systemic exposures of imatinib and bosutinib were predicted in silico using PBPK simulations.. Curcumin demonstrated potent reversible inhibition of cytochrome P450 (CYP)3A4-mediated N-demethylation of imatinib and bosutinib and CYP2C8-mediated metabolism of imatinib with inhibitory constants (k. A PBPK model for curcumin in a SLN formulation was successfully developed. Although curcumin possesses a strong In Vitro inhibitory activity towards CYP3A4 and CYP2C8 enzymes, its interactions with imatinib and bosutinib were unlikely to be of clinical importance due to curcumin's poor bioavailability.

Topics: Aniline Compounds; Chromatography, High Pressure Liquid; Curcumin; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Glucuronides; Humans; Hydroxylation; Imatinib Mesylate; Microsomes, Liver; Models, Biological; Models, Molecular; Nitriles; Paclitaxel; Quinolines; Tandem Mass Spectrometry

Breast cancer (BCa) bone metastases (BMETs) drive osteolysis via a feed-forward loop involving tumoral secretion of osteolytic factors (e.g., PTHrP) induced by bone-matrix-derived growth factors (e.g., TGFβ). In prior experiments, turmeric-derived curcumin inhibited in vivo BMET progression and in vitro TGFβ/Smad-signaling in a TGFβ-stimulated PTHrP-dependent human xenograft BCa BMET model (MDA-SA cells). However, it is unclear whether curcumin or curcumin-glucuronide mediates in vivo protection since curcumin-glucuronide is the primary circulating metabolite in rodents and in humans. Thus, effects of curcumin vs. curcumin-glucuronide on Smad-dependent TGFβ signaling were compared in a series of BCa cell lines forming TGFβ-dependent BMET in murine models, and tissue-specific metabolism of curcumin in mice was examined by LC-MS. While curcumin inhibited TGFβ-receptor-mediated Smad2/3 phosphorylation in all BCa cells studied (human MDA-SA, MDA-1833, MDA-2287 and murine 4T1 cells), curcumin-glucuronide did not. Similarly, curcumin, but not curcumin-glucuronide, blocked TGFβ-stimulated secretion of PTHrP from MDA-SA and 4T1 cells. Because the predominant serum metabolite, curcumin-glucuronide, lacked bioactivity, we examined tissue-specific metabolism of curcumin in mice. Compared to serum and other organs, free curcumin (both absolute and percentage of total) was significantly increased in bone, which was also a rich source of enzymatic deglucuronidation activity. Thus, curcumin, and not curcumin-glucuronide, appears to inhibit bone-tropic BCa cell TGFβ-signaling and to undergo site-specific activation (deconjugation) within the bone microenvironment. These findings suggest that circulating curcumin-glucuronide may act as a prodrug that preferentially targets bone, a process that may contribute to the bone-protective effects of curcumin and other highly glucuronidated dietary polyphenols.

Topics: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Bone Neoplasms; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Glucuronides; Humans; Mice; Mice, Inbred C57BL; Parathyroid Hormone-Related Protein; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Curcumin is a major component of the spice turmeric ( Curcuma longa), often used in food or as a dietary supplement. Many preclinical studies on curcumin suggest health benefits in many diseases due to its antioxidant/anti-inflammatory and epigenetic effects. The few human studies and curcumin's unfavorable pharmacokinetics (PK) have limited its potential, leading researchers to study and develop formulations to improve its PK. The purpose of this clinical study is to describe the acute pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received a 4 g dose of curcumin capsules with a standard breakfast. Plasma samples were collected at specified time points and analyzed for curcumin and its glucuronide levels. RNA was extracted from leukocytes and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were below the detection limit by HPLC-ITMS/MS/MS. However, curcumin-O-glucuronide (COG), a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and some levels of metabolite are in line with previous studies. PD marker antioxidant genes NRF2, HO-1, and NQO1 and epigenetic genes HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. COG PK is well-described by a one-compartment model, and the PK/PD of COG and its effect on antioxidant and epigenetic gene expression are captured by an indirect response model (IDR). A structural population PK model was sequentially established using a nonlinear mixed-effect model program (Monolix Lixoft, Orsay, France). Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with the observed data. Taken together, these results show that the bioavailability of the parent curcumin compound is low, and oral administration of curcumin can still deliver detectable levels of curcumin glucuronide metabolite. But most importantly, it elicits antioxidant and epigenetic effects which could contribute to the overall health beneficial effects of curcumin.

Topics: Administration, Oral; Adolescent; Adult; Antioxidants; Biological Availability; Capsules; Curcuma; Curcumin; Epigenesis, Genetic; Female; Gene Expression Regulation; Glucuronides; Healthy Volunteers; Heme Oxygenase-1; Histone Deacetylases; Humans; Male; Models, Biological; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Plant Extracts; Young Adult

Oral consumption of curcumin, a natural polyphenol, is associated with reduced incidence of cancer. Yet, a significant amount of the orally dosed compound is eliminated in the feces, and a major fraction of the absorbed compound is metabolized to inactive glucuronides, resulting in poor bioavailability (<1%). It is not known how oral curcumin exhibits chemopreventive activity. We propose curcumin glucuronide is an inflammation-responsive natural prodrug that is converted back to curcumin on demand at the site of action. Our studies show elevated levels of β-glucuronidase, an enzyme that hydrolyzes the glycosidic bond of glucuronides to generate the parent compound, in human breast cancer. Oral administration of curcumin in mouse tumor models generated significant tumor levels of the polyphenol. Intravenous administration of the glucuronide resulted in the formation of curcumin in the tumor tissue. Chronic daily oral curcumin dosing led to tumor accumulation of curcumin and inhibition of tumor growth in tumor models with high β-glucuronidase activity. Overall, the study presented here provides preliminary evidence for a novel mechanism of action for orally administered curcumin.-Liu, G., Khanna, V., Kirtane, A., Grill, A., Panyam, J. Chemopreventive efficacy of oral curcumin: a prodrug hypothesis.

Topics: Administration, Oral; Animals; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Female; Glucuronidase; Glucuronides; Humans; Mice, Inbred BALB C; Mice, Nude; Prodrugs

Curcumin (from turmeric), has been extensively investigated for potential beneficial properties in numerous diseases. Most work has focused on supra-dietary concentrations/doses that would necessitate curcumin supplementation. However, much evidence instigating curcumin research is underpinned by epidemiological data based on low dietary intake via turmeric consumption.. Here, a novel, highly sensitive liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) method for detection of curcuminoids is described. Assay sensitivity is demonstrated in a pilot pharmacokinetic volunteer study following ingestion of foodstuffs containing a standardized mass of turmeric, representative of daily consumption by certain South Asian populations. Free parent curcumin was detectable in plasma from one individual, reaching maximal plasma concentrations (C. Despite poor absorption and rapid conjugation, dietary intake of standard culinary turmeric within complex food matrices furnished human plasma with detectable levels of curcuminoids. Whether sustained low systemic concentrations of these non-nutritive, biologically active, dietary components may have pharmacological activity for human health benefit, warrants further research.

Topics: Adult; Calibration; Chromatography, Liquid; Curcuma; Curcumin; Diarylheptanoids; Female; Food Analysis; Glucuronides; Healthy Volunteers; Humans; Limit of Detection; Male; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

Human mast cell tryptase has been shown as an activating enzyme in matrix degradation process. The previous study suggest that tryptase either alone or in joining with activation of metalloproteinases, can associate in extra cellular matrix damage and the possible destruction of the basement membrane resulting in photoaging. Therefore the inhibition of tryptase activity is one of the most important therapeutic strategies against the photoaging. Curcumin has been shown to be a potential agent for preventing and/or treating the photoaging induced by UV radiation. However, the protective effect of curcumin against the photoaging through the tryptase inhibition is still inadequately understood. In this work, computational methods to characterize the structural framework and define the atomistic details of the determinants for the tryptase inhibition mechanism by curcuminoids were performed. By molecular docking, three putative binding models able to efficiently bind all curcuminoids were identified. Analysis of molecular dynamics simulations revealed that cyclocurcumin, curcumin glucuronide, and curcumin, the most effective inhibitors from the three models, modified significant tryptase monomer rigidity by binding in all the possible sites. The result of these binding events is the suppression of the functional enzymatic motions involving the binding of substrates to the catalytic site. On the basis of this finding may thus be beneficial for the development of new natural inhibitors for the therapeutic remedy of photoaging, targeting and modulating the activity of tryptase.

Topics: Curcumin; Glucuronides; Humans; Molecular Docking Simulation; Protein Domains; Structure-Activity Relationship; Tryptases

Curcumin, a polyphenol derived from the rhizome of the naturally occurring plant Curcuma longa, has various pharmacological actions such as antioxidant and anti-inflammatory effects. In this paper, we evaluated the role of its internal metabolite, curcumin β-D-glucuronide (curcumin monoglucuronide, CMG), by investigating curcumin kinetics and metabolism in the blood. Firstly, we orally administered highly bioavailable curcumin to rats to elucidate its kinetics, and observed not only the free-form of curcumin, but also, curcumin in a conjugated form, within the portal vein. We confirmed that curcumin is conjugated when it passes through the intestinal wall. CMG, one of the metabolites, was then orally administered to rats. Despite its high aqueous solubility compared to free-form curcumin, it was not well absorbed. In addition, CMG was injected intravenously into rats in order to assess its metabolic behavior in the blood. Interestingly, high levels of free-form curcumin, thought to be sufficiently high to be pharmacologically active, were observed. The in vivo antitumor effects of CMG following intravenous injection were then evaluated in tumor-bearing mice with the HCT116 human colon cancer cell line. The tumor volume within the CMG group was significantly less than that of the control group. Moreover, there was no significant loss of body weight in the CMG group compared to the control group. These results suggest that CMG could be used as an anticancer agent without the serious side effects that most anticancer agents have.

Topics: Administration, Intravenous; Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Biological Availability; Curcumin; Glucuronides; Humans; Intestinal Absorption; Intestinal Mucosa; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Portal Vein; Prodrugs; Rats; Rats, Sprague-Dawley; Weight Loss

Curcumin is a bioactive molecule extracted from Turmeric roots that has been recognized to possess a wide variety of important biological activities. Despite its great pharmacological activities, curcumin is highly hydrophobic, which results in poor bioavailability. We have formulated this hydrophobic compound into stable polymeric nanoparticles (nano-curcumin) to enhance its oral absorption. Pharmacokinetic analysis after oral delivery of nano-curcumin in mice demonstrated approximately 20-fold reduction in dose requirement when compared to unformulated curcumin to achieve comparable plasma and central nervous system (CNS) tissue concentrations. This investigation corroborated our previous study of curcumin functionality of attenuating opioid tolerance and dependence, which shows equivalent efficacy of low-dose (20mg/kg) nano-curcumin and high-dose (400mg/kg) pure curcumin in mice. Furthermore, the highly selective and validated liquid chromatography-mass spectrometry (LC-MS) method was developed to quantify curcumin glucuronide, the major metabolite of curcumin. The results suggest that the presence of curcumin in the CNS is essential for prevention and reversal of opioid tolerance and dependence.

Topics: Administration, Oral; Animals; Biological Availability; Brain; Curcumin; Drug Delivery Systems; Glucuronides; Male; Mice; Mice, Inbred ICR; Nanoparticles; Spinal Cord

We have previously shown that curcumin (CUR) may increase lipid accumulation in cultured human acute monocytic leukaemia cell line THP-1 monocytes/macrophages, but that tetrahydrocurcumin (THC), an in vivo metabolite of CUR, has no such effect. In the present study, we hypothesised that the different cellular uptake and/or metabolism of CUR and THC might be a possible explanation for the previously observed differences in their effects on lipid accumulation in THP-1 monocytes/macrophages. Chromatography with tandem MS revealed that CUR was readily taken up by THP-1 monocytes/macrophages and slowly metabolised to hexahydrocurcumin sulphate. By contrast, the uptake of THC was low. In parallel with CUR uptake, increased lipid uptake was observed in THP-1 macrophages but not with the uptake of THC or another CUR metabolite and structurally related compounds. From these results, it is possible to deduce that CUR and THC are taken up and metabolised differently in THP-1 cells, which determine their biological activity. The remarkable differential cellular uptake of CUR, relative to THC and other similar molecules, may imply that the CUR uptake into cells may occur via a transporter.

Topics: Biological Transport; Carcinogens; Cell Differentiation; Cell Line; Chromatography, High Pressure Liquid; Curcumin; Diarylheptanoids; Glucuronides; Humans; Kinetics; Lipid Metabolism; Macrophages; Monocytes; Sulfates; Tandem Mass Spectrometry; Tetradecanoylphorbol Acetate

Curcumin, the yellow pigment in turmeric, has been shown to prevent malignancies in a variety of tissues in rodents, especially in the intestinal tract. Pharmacological activities of curcumin in cells in situ germane to chemoprevention, such as inhibition of expression of cyclooxygenase-2 (COX-2), require drug concentrations in the 10(-5) - 10(-4) M range. The systemic bioavailability of curcumin is low, so that its pharmacological activity may be mediated, in part, by curcumin metabolites. To investigate this possibility, we compared curcumin metabolism in human and rat hepatocytes in suspension with that in rats in vivo. Analysis by high-performance liquid chromatography with detection at 420 and 280 nm permitted characterization of metabolites with both intact diferoylmethane structure and increased saturation of the heptatrienone chain. Chromatographic inferences were corroborated by mass spectrometry. The major metabolites in suspensions of human or rat hepatocytes were identified as hexahydrocurcumin and hexahydrocurcuminol. In rats, in vivo, curcumin administered i.v. (40 mg/kg) disappeared from the plasma within 1 h of dosing. After p.o. administration (500 mg/kg), parent drug was present in plasma at levels near the detection limit. The major products of curcumin biotransformation identified in rat plasma were curcumin glucuronide and curcumin sulfate whereas hexahydrocurcumin, hexahydrocurcuminol, and hexahydrocurcumin glucuronide were present in small amounts. To test the hypothesis that curcumin metabolites resemble their progenitor in that they can inhibit COX-2 expression, curcumin and four of its metabolites at a concentration of 20 microM were compared in terms of their ability to inhibit phorbol ester-induced prostaglandin E2 (PGE2) production in human colonic epithelial cells. Curcumin reduced PGE2 levels to preinduction levels, whereas tetrahydrocurcumin, previously shown to be a murine metabolite of curcumin, hexahydrocurcumin, and curcumin sulfate, had only weak PGE2 inhibitory activity, and hexahydrocurcuminol was inactive. The results suggest that (a) the major products of curcumin biotransformation by hepatocytes occur only at low abundance in rat plasma after curcumin administration; and (b) metabolism of curcumin by reduction or conjugation generates species with reduced ability to inhibit COX-2 expression. Because the gastrointestinal tract seems to be exposed more prominently to unmetabolized curcumin than any other tissue, the

Topics: Adult; Animals; Anticarcinogenic Agents; Chromatography, High Pressure Liquid; Colon; Curcumin; Cyclooxygenase 2; Dinoprostone; Drug Interactions; Epithelial Cells; Female; Glucuronides; Hepatocytes; Humans; Intestinal Mucosa; Isoenzymes; Male; Mass Spectrometry; Membrane Proteins; Middle Aged; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred F344; Tetradecanoylphorbol Acetate