beta-carotene and Chemical-and-Drug-Induced-Liver-Injury

Erythropoietic protoporphyria is a rare photodermatosis for which treatment options are limited. The present report describes the clinical features of a patient with erythropoietic protoporphyria and liver function test abnormalities associated with treatment with beta-carotene. Subsequent treatment with narrow-band UVB phototherapy resulted in marked subjective improvement in photosensitivity, which was confirmed by abolition of demonstrated abnormalities on monochromator phototesting. The therapeutic options for photosensitivity in erythropoietic protoporphyria are reviewed and discussed.

Topics: Antioxidants; beta Carotene; Canthaxanthin; Chemical and Drug Induced Liver Injury; Child; Feces; Humans; Male; Porphyria, Hepatoerythropoietic; Protoporphyrins; Ultraviolet Rays; Ultraviolet Therapy

Recent investigations have begun to define more clearly the cellular and molecular roles of oxidant stress in mediating the liver injury and fibrosis of metal storage diseases. Because of a variety of perturbations in antioxidant homeostasis in iron and copper overload, restoring the antioxidant balance to normal, or even exceeding normal levels of selected antioxidants, may provide additional protection against liver injury and prevent the progression to fibrosis and cirrhosis. Inasmuch as GSH levels appear to be elevated in livers of experimentally iron-overloaded animals, attempts to increase this antioxidant should perhaps be limited to copper overload conditions in which hepatic GSH is low. Vitamin C (ascorbate) supplementation should probably be avoided in all metal overload states because of its potentiation of radical generation by transition metals. The safety of beta-carotene in alcoholic liver disease has been questioned. Therefore, until more is known about its toxicity in metal overload, beta-carotene may not be an ideal antioxidant for clinical trials. Vitamin E and related compounds, therefore, appear to be the most reasonable antioxidants to test in metal overload states at this time. In the near future, the results of controlled clinical trials of the use of antioxidants in these and other liver disorders will hopefully provide clearer guidelines for their safety and possible use.

Topics: Animals; Antioxidants; Ascorbic Acid; beta Carotene; Carotenoids; Chemical and Drug Induced Liver Injury; Copper; Glutathione; Iron; Liver Cirrhosis, Experimental; Liver Diseases; Liver Diseases, Alcoholic; Metals; Oxidative Stress; Vitamin E

Acute liver injury (ALI), posing a serious threaten to our life, has emerged as a public health issue around the world. β-carotene has plenty of pharmacologic effects, such as anti-inflammatory, antioxidant, and antitumor activities. In this study, we focused on studying the protective role and potential molecular mechanisms of β-carotene against D-galactosamine (D-GalN) and lipopolysaccharide (LPS) induced ALI. Our results indicated that β-carotene pretreatment effectively hindered abnormal changes induced by LPS/D-GalN in liver histopathology. Meanwhile, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were downgraded with β-carotene pretreatment. β-carotene pretreatment also decreased malondialdehyde content and myeloperoxidase activity, increased glutathione peroxidase and superoxide dismutase levels, and reduced the levels of tumor necrosis factor-a (TNF-α) and interleukin 6 (IL-6) in liver tissues. Further investigations found that β-carotene mediated multiple signaling pathways in LPS/D-GalN-induced ALI, inhibiting NF-κB and MAPK signaling and upregulating the expression of Nrf2 and HO-1 proteins. All findings indicate that β-carotene appears to protect mice against LPS/D-GalN induced ALI by reducing oxidative stress and inflammation, possibly via regulating NF-κB, MAPK, and Nrf2 signaling.

Topics: Animals; Antioxidants; beta Carotene; Chemical and Drug Induced Liver Injury; Galactosamine; Lipopolysaccharides; Liver; Mice; NF-E2-Related Factor 2; NF-kappa B; Tumor Necrosis Factor-alpha

Bromobenzene is a compound which has contributed much in understanding the mechanisms involved in xenobiotic hepatotoxicity induced by drugs and environment pollutants. In the present study, the protective and ameliorative effect of beta-carotene was investigated against bromobenzene-induced hepatotoxicity and compared with silymarin, a standard hepatoprotective reference drug. Beta-carotene (10 mg/kg b.w. p.o.) was administered to the rats for 9 days before intragastric intubation of bromobenzene (10 mmol/kg b.w.). Liver marker enzymes (aspartate transaminase, alanine transaminase and alkaline phosphatase), total protein content, bilirubin, total cholesterol, high-density lipoproteins, triglycerides, antioxidant status (reduced glutathione, superoxide dismutase, catalase, glutathione-S-transferase and glutathione peroxidase) were assessed along with histopathological analysis. ELISA was performed for analysing the levels of cytokines such as TNF-α, IL-1β and IL-6 in serum and in the liver. Caspase-3, COX-2 and NF-κB were evaluated by Western blotting. Administration of bromobenzene resulted in elevated levels of liver marker enzymes, bilirubin, lipid peroxidation and cytokines but deterioration in total protein content, antioxidant levels and histopathological conditions. Pre-treatment with beta-carotene not only significantly decreased the levels of liver markers, lipid peroxidation and cytokines but also improved histo-architecture and increased antioxidant levels minimising oxidative stress, and reduced factors contributing to apoptosis. This significant reversal of the biochemical changes on pre-treatment with beta-carotene in comparison with rats administered with bromobenzene clearly demonstrates that beta-carotene possesses promising hepatoprotective effect through its antioxidant, anti-inflammatory and antiapoptotic activity and hence is suggested as a potential therapeutic agent for protection from bromobenzene.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; beta Carotene; Bilirubin; Bromobenzenes; Chemical and Drug Induced Liver Injury; Cytokines; Female; Protective Agents; Rats; Rats, Wistar

Brain damage is a major complication of fulminant hepatic failure. d-Galactosamine (d-GalN)-induced liver toxicity causes damage to brain. The effects of vitamins and selenium mixture against d-GalN stimulated brain injury were investigated in this study. Sprague-Dawley female rats aged 2.0-2.5 months were used for the study. The rats were divided into four categories. A 0.9% NaCl solution was intraperitoneally given to the experimental rats in the first group. Using gavage technique, the second group of animals were subjected to a formulation consisting of 100 mg·kg

Topics: alpha-Tocopherol; Animals; Ascorbic Acid; beta Carotene; Brain; Brain Injuries; Chemical and Drug Induced Liver Injury; Female; Galactosamine; Rats; Rats, Sprague-Dawley; Selenium

In this study, the protective role of β-carotene against ammonium sulfate-induced toxicity has been evaluated in Mus musculus var. albino mice, along with biochemical and histopathological parameters. Some biochemical parameters such as aspartate transaminase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), creatinine and oxidative stress parameters, malondialdehyde (MDA), and glutathione (GSH) levels in kidney and liver tissues were investigated. The mice were randomly divided into six groups. Group I received intraperitoneal injections of 0.9% NaCl; group II received orally administered 250 mg kg

Topics: Alanine Transaminase; Ammonium Sulfate; Animals; Aspartate Aminotransferases; beta Carotene; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Glutathione; Humans; Kidney; Liver; Male; Malondialdehyde; Mice; Oxidative Stress

Isoniazid (INH) and Rifampicin (RIF) are known hepatotoxic agents. We compared the efficacy of Spirulina fusiformis and its active components vitamin B12 and beta-carotene in attenuating INH and RIF induced hepatotoxicity. We also tried to elucidate the inflammatory mechanism behind anti-tuberculosis drug induced hepatotoxicity. INH and RIF were administered to Wistar albino rats for 28 days to induce hepatotoxicity. S. fusiformis, vitamin B12, and beta-carotene were co-administered with INH and RIF and their hepatoprotective, antioxidant, and immunomodulatory roles were studied through blood and liver analysis. Changes induced by INH and RIF in antioxidants, cytokines (IL-6 and IL-10) and expression of Nuclear Factor-κB (NF-κB) and Nitric Oxide Synthase (iNOS) were also studied. Supplement treatment caused restoration of liver function parameters to normal levels along with reversal of inflammatory changes in IL-6 and IL-10 levels. Liver PCNA, iNOS, and NF-κB expression were reduced in the supplement treated tissues compared to INH and RIF treated rats as evidenced by immunohistochemistry and quantitative PCR. Correlation of IL-6 levels, PCNA, and iNOS with NF-κB showed its pivotal role in the inflammatory process. Study shows the pivotal role of NF-kB and the equivalence in antioxidant efficacy of vitamin B12 and beta-carotene compared to Spirulina fusiformis. J. Cell. Biochem. 118: 3825-3833, 2017. © 2017 Wiley Periodicals, Inc.

Topics: Animals; Antitubercular Agents; beta Carotene; Chemical and Drug Induced Liver Injury; Dietary Supplements; Female; Interleukin-10; Interleukin-6; Liver; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Wistar; Spirulina; Vitamin B 12

Angiotensin II is one of the key regulatory peptides implicated in the pathogenesis of liver disease. The mechanisms underlying the salubrious role of α-tocopherol and β-carotene on liver pathology have not been comprehensively assessed. Here, we investigated the mechanisms underlying the role of Angiotensin II on hepatic damage and if α-tocopherol and β-carotene supplementation attenuates hepatic damage. Hepatic damage was induced in Apoe(-/-)mice by infusion of Angiotensin II followed by oral administration with α-tocopherol and β-carotene-enriched diet for 60 days. Investigations showed fibrosis, kupffer cell hyperplasia, hepatocyte degeneration and hepatic cell apoptosis; sinusoidal dilatation along with haemorrhages; evidence of fluid accumulation; increased ROS level and increased AST and ALT activities. In addition, tPA and uPA were down-regulated due to 42-fold up-regulation of PAI-1. MMP-2, MMP-9, MMP-12, and M-CSF were down-regulated in Angiotensin II-treated animals. Notably, α-tocopherol and β-carotene treatment controlled ROS, fibrosis, hepatocyte degeneration, kupffer cell hyperplasia, hepatocyte apoptosis, sinusoidal dilatation and fluid accumulation in the liver sinusoids, and liver enzyme levels. In addition, PAI-1, tPA and uPA expressions were markedly controlled by β-carotene treatment. Thus, Angiotensin II markedly influenced hepatic damage possibly by restraining fibrinolytic system. We concluded that α-tocopherol and β-carotene treatment has salubrious role in repairing hepatic pathology.

Topics: alpha-Tocopherol; Angiotensin II; Animals; Apolipoproteins E; beta Carotene; Chemical and Drug Induced Liver Injury; Gene Expression Regulation; Liver; Mice; Mice, Knockout; Reactive Oxygen Species

The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma membrane domain of hepatocytes, which mediates active transport of unconjugated and conjugated bile salts from liver cells into bile. BSEP activity therefore plays an important role in bile flow. In humans, genetically inherited defects in BSEP expression or activity cause cholestatic liver injury, and many drugs that cause cholestatic drug-induced liver injury (DILI) in humans have been shown to inhibit BSEP activity in vitro and in vivo. These findings suggest that inhibition of BSEP activity by drugs could be one of the mechanisms that initiate human DILI. To gain insight into the chemical features responsible for BSEP inhibition, we have used a recently described in vitro membrane vesicle BSEP inhibition assay to quantify transporter inhibition for a set of 624 compounds. The relationship between BSEP inhibition and molecular physicochemical properties was investigated, and our results show that lipophilicity and molecular size are significantly correlated with BSEP inhibition. This data set was further used to build predictive BSEP classification models through multiple quantitative structure-activity relationship modeling approaches. The highest level of predictive accuracy was provided by a support vector machine model (accuracy = 0.87, κ = 0.74). These analyses highlight the potential value that can be gained by combining computational methods with experimental efforts in early stages of drug discovery projects to minimize the propensity of drug candidates to inhibit BSEP.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Humans; Quantitative Structure-Activity Relationship

In the present study, in vitro antioxidant, antioxidative stress and hepatoprotective activity of Moringa oleifera Lam. seed oil (Ben oil; BO) was evaluated against carbon tetrachloride (CCl(4) ) induced lipid peroxidation and hepatic damage in rats. The oil at 0.2 and 0.4 mL/rat was administered orally for 21 consecutive days. The substantially elevated serum enzymatic (GOT, GPT, ALP, GGT) and bilirubin levels were significantly restored towards normalization by the oil. There was a significant elevation in the level of malondialdehyde (MDA), non-protein sulfhydryl (NP-SH), and total protein (TP) contents in the liver tissue. The results obtained indicated that BO possesses potent hepatoprotective action against CCl(4) -induced hepatic damage by lowering liver marker enzymes, MDA concentration, and elevating NP-SH and TP levels in liver tissue. The biochemical observations were supplemented with histopathological examination of rat liver. The results of this study showed that treatment with Ben oil or silymarin (as a reference) appears to enhance the recovery from hepatic damage induced by CCl(4) . The pentobarbital induced narcolepsy prolongation in mice was retarded by the Ben oil. Acute toxicity test in mice showed no morbidity or mortality. In vitro DPPH radical scavenging and β-carotene-linolic acid assay tests of the BO exhibited a moderate antioxidant activity in both tests used. The possible mechanism(s) of the liver protective activity of Ben oil activity may be due to free radical scavenging potential caused by the presence of antioxidant component(s) in the oil. Consequently, BO can be used as a therapeutic regime in treatment of some hepatic disorders.

Topics: Animals; Antioxidants; beta Carotene; Bilirubin; Biphenyl Compounds; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Female; Linoleic Acid; Lipid Peroxidation; Liver; Male; Malondialdehyde; Mice; Moringa oleifera; Picrates; Plant Oils; Rats; Rats, Wistar; Seeds; Silymarin

The in vitro hepatoprotective effect of the methanolic extract from Ficus gnaphalocarpa (Miq.) Steud. ex A. Rich (Moraceae) on the CCl₄-induced liver cell damage as well as the possible antioxidant mechanisms involved in this protective effect, were investigated. The phytochemical investigation of this methanolic extract led to the isolation of six compounds identified as: betulinic acid (1); 3-methoxyquercetin (2); catechin (3); epicatechin (4); quercetin (5); and quercitrin (6). The hepatoprotective activity of these compounds was tested in vitro against CCl₄-induced damage in rat hepatoma cells. In addition, radical-scavenging activity, β-carotene-linoleic acid model system, ferric-reducing antioxidant parameter and microsomal lipid peroxidation assays were used to measure antioxidant activity of crude extract and isolated compounds. Silymarin and trolox were used as standard references and, respectively, exhibited significant hepatoprotective and antioxidant activities. (5), (6) and (2) showed significant antioxidant and hepatoprotective activities as indicated by their ability to prevent liver cell death and lactate dehydrogenase leakage during CCl₄ intoxication. These results suggest that the protective effects of crude extract of F. gnaphalocarpa against the CCl₄-induced hepatotoxicity possibly involve the antioxidant effect of these compounds.

Topics: Animals; Antioxidants; beta Carotene; Cell Death; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; Chromans; Ficus; Free Radical Scavengers; L-Lactate Dehydrogenase; Linoleic Acid; Lipid Peroxidation; Liver; Methanol; Microsomes, Liver; Plant Extracts; Rats; Silymarin

Water spinach (Ipomoea aquatica Forsk; I. aquatica) of the green-stemmed type (green type) is widely consumed, but there also exists a red-stemmed variety (red type). In the present study, the antioxidant capacity of the red type was compared to that of the green type in carbon tetrachloride (CCl(4))-treated mice. CCl(4)-induced thiobarbituric acid reactive substrate (TBARS) formation in the liver was significantly suppressed in mice fed 5% red-type I. aquatica, while the green type showed no effect. Hydrophobic oxygen radical absorbance capacity (H-ORAC(FL)) in the red type showed a lower level than that in the green type; however, lipophilic ORAC (L-ORAC(FL)) and total-ORAC(FL) levels were significantly higher in the red type than in the green type. α-Tocopherol, anthocyanidin/proanthocyanidin, and β-carotene contents were all significantly higher in the red type than in the green type. These results suggest that the wild red-type I. aquatica contains certain lipophilic components that exert antioxidant capacities not only in vitro but also in vivo. Such effective components in the red type would be beneficial phytochemicals for suppressing several diseases related to oxidative stress.

Topics: alpha-Tocopherol; Animals; Anthocyanins; Antioxidants; beta Carotene; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Ipomoea; Liver; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Phytotherapy; Plant Extracts; Plant Stems; Species Specificity; Thiobarbituric Acid Reactive Substances

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

In this study, the authors aimed to investigate the role of oxidative stress on the hepatic damage caused by methotrexate (MTX) and the possible protective effects of beta-carotene against this damage. The rats were divided into four groups as control, MTX (20 mg/kg ip), beta-carotene (10 mg/kg/day ip) + MTX, and beta-carotene. Histopathologic alterations were evaluated for defining the liver damage. The tissue, malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GP-x) contents and serum aspartate aminotransferase (AST) and alanine aminotranferase (ALT) activities were also examined. Histopathologic damage for each group score findings have been determined as control: 0.66 +/- 0.33; MTX: 7.0 +/- 0.68; beta-carotene + MTX: 3.3 +/- 0.42; and beta-carotene: 0.5 +/- 0.3. In the MTX-treated group, MDA, AST, and ALT values were increased, while SOD and GP-x values were decreased compared with the control group. In the beta-carotene + MTX-treated group, AST and ALT values significantly decreased, while all other parameters were similar to the control group. This study shows that beta-carotene has a protective effect on MTX-induced oxidative hepatic damage. Consequently, it seems that an antioxidant agents like beta-carotene may be useful in decreasing the side effects of chemotherapy.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; beta Carotene; Chemical and Drug Induced Liver Injury; Glutathione Peroxidase; Histocytochemistry; Lipid Peroxidation; Liver; Malondialdehyde; Methotrexate; Microscopy; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Statistics, Nonparametric; Superoxide Dismutase

D-Galactosamine (D-GaIN) is a highly selective hepatotoxin that causes liver injury similar to human viral hepatitis via depletion of uridine nucleotides, which subsequently diminishes synthesis of RNA and proteins. The aim of this study was to investigate the role of selenium, ascorbic acid, beta-carotene, and alpha-tocopherol on D-GaIN-induced liver injury of rats by morphological and immunohistochemical means. In this study, Sprague-Dawley female rats were divided into four groups. Group I consists of rats injected physiologic saline solution intraperitoneally. Group II consists of rats given selenium (0.2 mg/kg per day), ascorbic acid (100 mg/kg per day), beta-carotene (15 mg/kg per day), and alpha-tocopherol (100 mg/kg per day) for 3 days via gavage method. Group III consists of the single dose of D-GaIN (500 mg/kg)-injected animals. Group IV are the D-GaIN-injected animals given the same antioxidant combination. In situ terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling (TUNEL) assay was applied to determine apoptosis for paraffin sections of the liver samples. Moreover, caspase-3 and proliferating cell nuclear antigen antibody were applied for paraffin sections. In the group given D-GaIN, apoptotic cells with TUNEL assays and caspase-3 activity, which are liver injury markers induced by D-GaIN, the hepatocyte proliferation with cell proliferation assay increased. However, selenium and other three antioxidants combination clearly suppressed an increase in apoptotic cells with TUNEL assay and caspase-3 activity. In addition, it suppressed D-GaIN-induced cell proliferation in the liver. As a result, these results indicate that selenium and three naturally occurring antioxidants shows a protective effect against liver injury induced by D-GaIN. These results suggest that supplementation with the combination of selenium, ascorbic acid, beta-carotene, and alpha-tocopherol may help prevent the development of liver injury.

Topics: alpha-Tocopherol; Animals; Antioxidants; Apoptosis; Ascorbic Acid; beta Carotene; Caspase 3; Cell Proliferation; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Galactosamine; Immunohistochemistry; In Situ Nick-End Labeling; Liver; Liver Diseases; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Selenium

Enzyme levels of serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT) and alkaline phosphatase (ALP) increased following paracetamol induction were significantly lowered due to pretreatment with the beta-carotene (BC). This supplementation reversed the trend inducing a significant decrease in bilirubin and urea levels. Paracetamol administration significantly reduced hepatic glycogen, glutathione (GSH), glutathione-S-transferase (GST), glutathione peroxidase (GPX) and glutathione reductase (GSH-R). Pretreatment of rats with BC significantly increased the enzyme activities. The results suggest hepatoprotective activity of BC.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Antioxidants; beta Carotene; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Liver; Rats; Rats, Wistar

The present study deals with evaluation of the hepatotoprotective activity of carotenoids from two well-known microalgae, Spirulina platensis and Dunaliella salina. Carotenoids were extracted in hexane:isopropyl alcohol (1:1 vol/vol) and fed orally in olive oil to Wistar albino rats at a dose of 100 microg/kg of body weight/day (in terms of carotenoids). The degree of hepatoprotection was measured by estimation of biochemical parameters like serum transaminases [serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT)], serum alkaline phosphatase, total albumin, and total protein. The results were compared with those for a control group, a CCl4-induced hepatic damage group, and a group treated with synthetic beta-carotene (all-trans) at the same dose. The protein content of the CCl4-treated group, which received normal diet and a dose of toxin, showed a significant decrease, i.e., 3.92 mg/mL, whereas the protein levels were higher, i.e., 6.96 and 6.32 mg/mL, in the case of the Dunaliella and Spirulina, respectively, carotenoid-treated groups. The CCl4-treated group shown higher activity of transaminases (128.68 units/mL SGPT and 171.52 units/mL SGOT). However, the activity of SGPT was 62.83 units/mL for Dunaliella and 76.83 units/mL for Spirulina, i.e., carotenoids of Dunaliella showed a higher degree of protection. For serum alkaline phosphatase, the standard beta-carotene value was 81.52 units/mL, compared with 84.46 units/mL for the CCl4-treated group; however, natural algal carotenoids yielded 38.45 units/mL (D. salina) and 44.73 units/mL (Spirulina). The total albumin value diminished with CCl4 treatment (2.46 mg/mL); the effect was highest for Dunaliella, followed by the Spirulina carotenoid-treated group. The results clearly indicate that carotenoids from Dunaliella possess better hepatoprotection compared with those from Spirulina. High-performance liquid chromatography of the carotenoids indicated that Spirulina contains only beta-carotene and Dunaliella contains other carotenoids and xanthophyll. The increase in protection with Dunaliella indicates that mixed carotenoids exhibit better biological activity than beta-carotene alone. The results of this study indicate that carotenoids obtained from an algal source have a higher antihepatotoxic effect, compared with synthetic beta-carotene and with beta-carotene alone from a natural source.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bacterial Proteins; beta Carotene; Blood Proteins; Carbon Tetrachloride; Carotenoids; Chemical and Drug Induced Liver Injury; Chlorophyta; Chromatography, High Pressure Liquid; Liver Diseases; Rats; Rats, Wistar; Serum Albumin; Spirulina; Xanthophylls

HP-1 a herbal formulation comprising of Phyllanthus niruri and extracts of Terminalia belerica, Terminalia chebula, Phyllanthus emblica and Tinospora cordifolia has been evaluated for hepatoprotective activity against carbon tetrachloride (CCl4) induced toxicity. Results show that HP-1 reversed the leakage of lactate dehydrogenase (LDH) and glutamate pyruvate transaminase (GPT) and prevented the depletion of glutathione (GSH) levels in a primary monolayer culture of rat hepatocytes (in vitro). HP-1 attenuated the serum toxicity as manifested in elevated levels of transaminases (glutamate oxaloacetate transaminase (GOT), and GPT) The antioxidative enzymes in liver (catalase and superoxide dismutase (SOD)) were restored to normal values after the oral administration of HP-1. HP-1 suppressed the formation of the superoxide anion radical and reduced CCl4 mediated lipid peroxidation (LPO). Silymarin and antioxidants (ascorbic acid, beta-carotene and alpha-tocopherol) were used for comparison. The present study showed that HP-1 is a potential hepatoprotective formulation with an additional attribute of being anti-peroxidative.

Topics: Administration, Oral; Alanine Transaminase; alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; beta Carotene; Carbon Tetrachloride; Cell Survival; Cells, Cultured; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Formazans; Glutathione; Hepatocytes; India; L-Lactate Dehydrogenase; Liver; Male; Phyllanthus; Phytotherapy; Plant Preparations; Plants, Medicinal; Rats; Silymarin; Terminalia; Tinospora

Astaxanthin is one of many carotenoids present in marine animals, vegetables and fruits. Since carotenoids are known to have antioxidant properties, we tested to determine if astaxanthin could have protective effects in the CCl4-treated rat liver by activating the antioxidant system. Astaxanthin blocked the increase of glutamate-oxalacetate transaminase (GOT) and glutamate-pyruvate transaminase (GTP) activity and thiobarbituric acid reactive substances (TBARS) in response to carbon tetrachloride (CCl4), while causing an increase in glutathione (GSH) levels and superoxide dismutase (SOD) activities in the CCl4-treated rat liver. These results suggest that astaxanthin protects liver damage induced by CCl4 by inhibiting lipid peroxidation and stimulating the cellular antioxidant system.

Topics: Adjuvants, Immunologic; Animals; beta Carotene; Body Weight; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Glutathione Reductase; Lipid Peroxidation; Liver; Male; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Xanthophylls

Some studies have indicated that the injury induced by the hepato- and pneumotoxin monocrotaline (MCT) is in part mediated by oxidation. Because beta-carotene is a potent antioxidant, we hypothesized that it would protect the lung and liver parenchyma against MCT-induced injury. Twenty rats were assigned randomly to four groups. All rats were fed a standard AIN93G diet with or without beta-carotene. After 1 week on the purified diets, half of the rats fed the control (standard) diet and half of the rats fed the beta-carotene-supplemented diet were injected subcutaneously with 60 mg MCT/kg body weight or its vehicle (water). All rats were sacrificed at 4 weeks. Histological examination showed that beta-carotene alone did not affect lung or liver structure. On the other hand, lungs of MCT-treated rats had severe focal pneumonia, extensive deposition of collagen in the septa, marked inflammation of the small arteries and arterioles, and arterialization of the small venules. Livers of MCT-treated rats showed some fatty infiltration and diffuse hemorrhages, more prominent sometimes in the centrilobular area and sometimes in the periportal region. Concomitant treatment with beta-carotene protected the lung parenchyma from the inflammatory reaction and the septal fibrosis, but did not prevent cardiac right ventricular hypertrophy and only slightly reduced the thickening of the wall of small arteries and arterioles. Incidence of steatosis and hemorrhages was decreased in the liver. These results indicate that MCT-induced pulmonary vascular remodeling occurs in the absence of inflammatory cell infiltration. Furthermore, beta-carotene prevented inflammation and protected the lung and liver parenchyma of MCT-treated rats.

Topics: Animals; Antidotes; Antioxidants; beta Carotene; Chemical and Drug Induced Liver Injury; Collagen; Diet; Fatty Liver; Hemorrhage; Hypertrophy, Right Ventricular; Liver; Lung; Lung Diseases; Male; Monocrotaline; Poisons; Rats; Rats, Sprague-Dawley

We previously reported the isolation of zeaxanthin and zeaxanthin dipalmitate using bioactivity-guided fractionation to discover hepatoprotective components of Lycium chinense against carbon tetrachloride induced hepatotoxicity. The present study was designed to uncover the effects of zeaxanthin dipalmitate on hepatic parenchymal and nonparenchymal cells in vitro. Uptake of [3H]thymidine by cultured rat Ito cells in response to zeaxanthin dipalmitate was measured. Collagen synthesis was assessed by the collagenase digestion method. The effects of zeaxanthin dipalmitate on the formation of nitric oxide (NO) and the release of tumor necrosis factor-alpha (TNF-alpha) from Kupffer cells and peritoneal macrophages were also assayed. Zeaxanthin dipalmitate showed a significant hepatoprotective activity against carbon tetrachloride toxicity. Cellular malondialdehyde (MDA) levels declined significantly with the treatment of the compound in a concentration dependent manner. Zeaxanthin dipalmitate significantly inhibited the uptake of [3H]thymidine by Ito cells. Zeaxanthin dipalmitate also reduced collagen synthesis in Ito cells by 65.1% (p < 0.05) as compared to untreated controls. The formation of NO in either Kupffer cells or in peritoneal macrophages was significantly decreased by zeaxanthin dipalmitate in a concentration dependent manner. The release of TNF-alpha was somewhat less affected by the compound. From these results, we conclude that zeaxanthin dipalmitate exerts a potent hepatoprotective activity by inhibiting Ito cell proliferation, collagen synthesis and by inhibiting certain biochemical functions of Kupffer cells.

Topics: Animals; beta Carotene; Carbon Tetrachloride; Cell Division; Cells, Cultured; Chemical and Drug Induced Liver Injury; Collagen; Kupffer Cells; Liver; Liver Diseases; Macrophages, Peritoneal; Male; Nitric Oxide; Palmitates; Plant Extracts; Plants, Medicinal; Rats; Rats, Wistar; Thymidine; Tritium; Tumor Necrosis Factor-alpha; Xanthophylls

The experiments on Wistar rats showed that beta-carotene and retinol acetate decreased the level of the biochemical signs of the hepatocyte injury and lowered or abolished the immunosuppressive effect induced by D-galactosamine. The hepatoprotective and immunomodulating effects of beta-carotene were higher. D-Galactosamine induced the development of the immunosuppressing properties in light erythrocytes and retinol acetate induced the development of the immunostimulating properties in heavy erythrocyte of the poisoned animals. beta-carotene prevented the development of the immunosuppressing properties in such cells. The immunomodulating effect of beta-carotene in the toxic affection of the liver was associated with blocking or retarding of the entry of the suppressing substances to the vascular channel from the hepatocytes and did not depend on their action on the erythrocytes.

Topics: Adjuvants, Immunologic; Animals; Antibody Formation; Antioxidants; beta Carotene; Chemical and Drug Induced Liver Injury; Erythrocytes; Galactosamine; Immunosuppressive Agents; Lipid Peroxidation; Rats; Rats, Wistar; Sheep; Stereoisomerism; Vitamin A

Earlier data from experiments in rats have shown that administration of retinyl esters (vitamin A) strongly influences the effects of CCl4 on the liver. The accumulation of collagen was inhibited, but an increase in CCl4-toxicity with high mortality was observed. The present study was conducted to examine the effects of beta-carotene (provitamin A) on CCl4-related general and hepatic toxicity in rats. Oral administration of beta-carotene during CCl4-treatment resulted, biochemically, in a significantly lower increase in the hydroxyproline liver content and, histopathologically, in less severe liver fibrosis as compared with the liver of rats not treated with beta-carotene. The study also showed that beta-carotene administration could prevent the long-term loss of retinoids from the CCl4-injured liver. No significant toxic effects of beta-carotene, as previously found with retinyl esters (vitamin A), were observed. This experimental study suggests that beta-carotene has the therapeutic potential to decrease the severity of liver fibrosis without marked toxicity.

Topics: Animals; beta Carotene; Carbon Tetrachloride Poisoning; Carotenoids; Chemical and Drug Induced Liver Injury; Collagen; Female; Hydroxyproline; Liver; Liver Cirrhosis, Experimental; Liver Function Tests; Rats; Rats, Inbred BN

Because we had found that ethanol interacts with retinol, we investigated whether it also affects its precursor, beta-carotene. In 14 baboons fed ethanol (50% of total energy) for 2 to 5 yr with a standard amount of beta-carotene (one 200-gm carrot/day), levels of beta-carotene were much higher than in controls fed isocaloric carbohydrate, both in plasma (122.5 +/- 30.9 nmol/dl vs. 6.3 +/- 1.4 nmol/dl; p less than 0.005) and in liver (7.9 +/- 1.1 nmol/gm vs. 1.8 +/- 0.5 nmol/gm; p less than 0.001). Even 20 days after withdrawal of the carrots, plasma beta-carotene levels remained higher in alcohol-fed baboons than in controls (10.1 +/- 3.8 nmol/dl vs. less than 0.1 nmol/dl). Next, the diet was supplemented with beta-carotene beadlets: in four pairs of baboons given a low dose of beta-carotene (3 mg/1,000 kcal), plasma levels were significantly higher in alcohol-fed animals than in controls, even when expressed per cholesterol (although the latter increased with alcohol intake). Seven pairs of animals were given a higher dose (30 mg/1,000 kcal) of beta-carotene for 1 mo, followed, in four pairs, by 45 mg for another month. On cessation of beta-carotene treatment, plasma levels decreased more slowly in the alcohol-fed baboons than in the controls. Percutaneous liver biopsy specimens revealed that liver concentrations of beta-carotene correlated with plasma levels but were higher in the alcohol-fed baboons than in the control baboons, whereas the beta-carotene-induced increase in liver retinoids was lower (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; beta Carotene; Carotenoids; Chemical and Drug Induced Liver Injury; Drug Interactions; Ethanol; Liver; Liver Diseases; Metabolic Clearance Rate; Papio