Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Short-term treatment of rats with hepatocarcinogens elicits a consistent pattern of phenotypic changes in hepatic drug metabolizing enzymes, the most striking of which is a marked increase in microsomal epoxide hydrolase (EH) activity. The antihistaminic drug methapyrilene induces a high incidence of hepatocellular carcinoma in F-344 rats. The studies reported here were designed to assess the effects of methapyrilene on hepatic EH activity, cytochrome P-450-dependent mixed-function oxidase activities, liver morphology, and liver-derived serum enzymes. Male F-344 rats were treated with three daily oral doses of methapyrilene-HCl, up to 300 mg/kg/day, and were sacrificed 48 hr after the last dose. Hepatic microsomal EH and cytosolic DT-diaphorase activities were increased in a dose-related fashion, to 420 and 230% of control, respectively. Cytochrome P-450 content and benzphetamine-N-demethylase and ethoxycoumarin-O-deethylase activities were concomitantly decreased to 35-50% of control. Serum gamma-glutamyl transpeptidase and alanine aminotransferase activities were elevated 22- to 27-fold, and serum bile acids to 36-fold by treatment with methapyrilene. Periportal lesions, characterized by inflammation, nuclear and nucleolar enlargement, bile duct hyperplasia, and hepatocellular necrosis, were observed following methapyrilene administration. The severity of the periportal lesion correlated with elevations in the serum chemistry parameters. The increases noted in microsomal EH activity supports the suggestion that this enzyme may be a useful biochemical marker for exposure to hepatocarcinogens.
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PMID:Effects of methapyrilene on rat hepatic xenobiotic metabolizing enzymes and liver morphology. 285 28

Recent metabolic studies have demonstrated the importance of reactive intermediates like quinones or semiquinone radicals in the covalent binding of halobenzenes to liver protein. The current studies were designed to examine if quinone intermediates are involved in the toxicity of hepatotoxic halobenzenes, bromobenzene (BB) and 1,2,4-trichlorobenzene (1,2,4-TCB). Two-electron reduction of the quinone intermediates by DT-diaphorase is considered to be a detoxication pathway since the resulting hydroquinone may be readily conjugated and excreted. Mice were pretreated with butylated hydroxyanisole (BHA; 0.5% in the diet, for 3 days), an inducer of DT-diaphorase, or dicoumarol (0.3 mmol/kg, p.o.), an inhibitor of this enzyme. The mice were then given BB (2.5 or 3.5 mmol/kg, i.p.) or 1,2,4-TCB (0.75 or 1.5 mmol/kg, i.p.). Dietary BHA markedly suppressed the hepatotoxicity caused by both BB and 1,2,4-TCB while dicoumarol significantly enhanced it, as judged by serum alanine aminotransferase activity. When mice were treated with BB at different times after the end of dietary BHA exposure, the degree of the protection against the hepatotoxicity appears to correlate to the extent of the induction of DT-diaphorase activity by BHA pretreatment. BHA pretreatment failed to protect against carbon tetrachloride-induced hepatotoxicity. These results seem to provide evidence for the involvement of the quinone metabolites in BB- and 1,2,4-TCB-induced hepatotoxicity and for the protective role of DT-diaphorase against the toxicity.
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PMID:Modulation of halobenzene-induced hepatotoxicity by DT-diaphorase modulators, butylated hydroxyanisole and dicoumarol: evidence for possible involvement of quinone metabolites in the toxicity of halobenzenes. 1009 53

Thymoquinone (TQ) is the major active component of the volatile oil of Nigella sativa seeds. The effects of TQ on carbon tetrachloride (CCl4)-induced hepatotoxicity was investigated in male Swiss albino mice. Carbon tetrachloride (20 microliters/Kg, i.p.) injected into mice, induced damage to liver cells and was followed by the increase in serum alanine aminotransferase (ALT) activity after 24 h. Oral administration of TQ in a single dose (100 mg/Kg) resulted in significant (p < 0.001) protection against the hepatotoxic effects of CCl4. TQ was tested as a substrate for mice hepatic DT-diaphorase in the presence of NADH. TQ appears to undergo reduction to dihydrothymoquinone (DHTQ). Reduction rates as a function of protein (liver homogenate) and substrate (TQ) concentrations are reported. An apparent K(m) of 0.1 mM and an apparent Vmax of 74 mumol/min/g liver were measured. TQ and DHTQ inhibited the in vitro non-enzymatic lipid peroxidation in liver homogenate (induced by Fe(3+)-ascorbate) in a dose dependent manner. In this in vitro model DHTQ was more potent in comparison with TQ and butylated hydroxytoluene (BHT). The IC50 for DHTQ, TQ and BHT were found to be 0.34, 0.87 and 0.58 microM respectively. The data suggest that the in vivo protective action of TQ against CCl4-induced hepatotoxicity may be mediated through the combined antioxidant properties of TQ and its metabolite DHTQ.
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PMID:Thymoquinone protects against carbon tetrachloride hepatotoxicity in mice via an antioxidant mechanism. 1009 55

Pretreating mice with schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, at a daily dose of 1 mmol/kg for 3 days protected against menadione-induced hepatic oxidative damage in mice, as evidenced by decreases in plasma alanine aminotransferase activity (78%) and hepatic malondialdehyde level (70%), when compared with the menadione intoxicated control. In order to define the biochemical mechanism involved in the hepatoprotection afforded by Sch B pretreatment, we examined the activity of DT-diaphorase (DTD) in hepatocytes isolated from Sch B pretreated rats. Hepatocytes isolated from Sch B pretreated (a daily dose of 1 mmol/kg for 3 days) rats showed a significant increase (25%) in DTD activity. The increase in DTD activity was associated with the enhanced rate of menadione elimination in the hepatocyte culture. The ensemble of results suggests that the ability of Sch B pretreatment to enhance hepatocellular DTD activity may at least in part be attributed to the protection against menadione hepatotoxicity.
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PMID:Schisandrin B protects against menadione-induced hepatotoxicity by enhancing DT-diaphorase activity. 1093 39

The protective and antioxidative effects of 2(3)tert-butyl-4-hydroxyanisole (BHA) against cardiotoxicity and hepatotoxicity induced by doxorubicin in mice were investigated. After pretreatment with different oral doses of BHA, doxorubicin 30 mg.kg-1 was given i.p. Serum GPT, GOT, LDH and CK were determined, and the mortality rate of animals was observed. Quinone reductase (QR), glutathione-S-transferases (GSTs) and glutathione reductase (GR) were determined on tissue cytosols with enzyme dynamic methods. Malondialdehyde (MDA) was measured by the method of thiobarbituric acid. Compared with the doxorubicin group, the serum GPT, GOT, LDH, CK and the mortality rate of mice were significantly decreased by BHA pretreatment, and BHA was shown to inhibit the increase of MDA induced by doxorubicin (P < 0.01 and P < 0.0001). Administration of BHA resulted in increased activities of QR, GSTs and GR in the myocardium and liver (P < 0.05 or P < 0.0001). These results suggest that BHA has protective effect against the toxicity induced by doxorubicin via the induction of QR, GSTs and GR activities and anti-lipid peroxidation.
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PMID:[Protective and antioxidative effect of 2(3)tert-butyl-4-hydroxyanisole against cytotoxicity induced by doxorubicin in mice]. 1201 38

Tea phenolic acids and catechins containing gallic acid moieties are most abundant in green tea, and various medical benefits have been proposed from their consumption. In the following, the cytotoxicities of these major tea phenolics toward isolated rat hepatocytes have been ranked and the mechanisms of cytotoxicity evaluated. The order of cytotoxic effectiveness found was epigallocatechin-3-gallate>propyl gallate>epicatechin-3-gallate>gallic acid, epigallocatechin>epicatechin. Using gallic acid as a model tea phenolic and comparing it with the tea catechins and gallic acid-derivative food supplements, the major cytotoxic mechanism found with hepatocytes was mitochondrial membrane potential collapse and ROS formation. Epigallocatechin-3-gallate was also the most effective at collapsing the mitochondrial membrane potential and inducing ROS formation. Liver injury was also observed in vivo when these tea phenolics were administered ip to mice, as plasma alanine aminotransferase levels were significantly increased. In contrast, GSH conjugation, methylation, metabolism by NAD(P)H:quinone oxidoreductase 1, and formation of an iron complex were important in detoxifying the gallic acid. In addition, for the first time, the GSH conjugates of gallic acid and epigallocatechin-3-gallate have been identified using mass spectrometry. These results add insight into the cytotoxic and cytoprotective mechanisms of the simple tea phenolic acids and the more complex tea catechins.
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PMID:Cellular and in vivo hepatotoxicity caused by green tea phenolic acids and catechins. 1760 63

To investigate the hepatotoxic potential of tienilic acid in vivo, we administered a single oral dose of tienilic acid to Sprague-Dawley rats and performed general clinicopathological examinations and hepatic gene expression analysis using Affymetrix microarrays. No change in the serum transaminases was noted at up to 1000 mg/kg, although slight elevation of the serum bile acid and bilirubin, and very mild hepatotoxic changes in morphology were observed. In contrast to the marginal clinicopathological changes, marked upregulation of the genes involved in glutathione biosynthesis [glutathione synthetase and glutamate-cysteine ligase (Gcl)], oxidative stress response [heme oxygenase-1 and NAD(P)H dehydrogenase quinone 1] and phase II drug metabolism (glutathione S-transferase and UDP glycosyltransferase 1A6) were noted after 3 or 6 h post-dosing. The hepatic reduced glutathione level decreased at 3-6 h, and then increased at 24 or 48 h, indicating that the upregulation of NF-E2-related factor 2 (Nrf2)-regulated gene and the late increase in hepatic glutathione are protective responses against the oxidative and/or electrophilic stresses caused by tienilic acid. In a subsequent experiment, tienilic acid in combination with l-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of Gcl caused marked elevation of serum alanine aminotransferase (ALT) with extensive centrilobular hepatocyte necrosis, whereas BSO alone showed no hepatotoxicity. The elevation of ALT by this combination was observed at the same dose levels of tienilic acid as the upregulation of the Nrf2-regulated genes by tienilic acid alone. In conclusion, these results suggest that the impairment of glutathione biosynthesis may play a critical role in the development of tienilic acid hepatotoxicity through extensive oxidative and/or electrophilic stresses.
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PMID:The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats. 1870 81

The hepatoprotective activity of kolaviron (KV), a biflavonoid complex from Garcinia kola seeds, and its purified fractions was investigated in mice intoxicated with carbon tetrachloride (CCl(4)). The ability of vitamin E to attenuate the toxicity was also examined. KV was extracted from powdered seeds of G. kola and then separated by thin-layer chromatography into three fractions--Fraction I (FI), Fraction II (FII), and Fraction III (FIII), with ratio of fronts values of 0.48, 0.71, and 0.76, respectively. Pretreatment with KV, FI, and FII at a dose of 100 mg/kg of body weight for 2 weeks and then challenge with CCl(4) at a dose of 1.2 g/kg of body weight, three times a week for 2 consecutive weeks, decreased the CCl(4)-induced increase in activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) by 31%, 30%, and 31% and 41%, 55%, and 42%, respectively. CCl(4) intoxication also caused a significant (P < .05) accumulation of lipid peroxidation (LPO) products as revealed by the formation of the thiobarbituric acid-reactive substances: CCl(4) induced LPO levels in serum and microsomes by 112% and 89%, respectively. However, pretreatment with KV, FI, and FII decreased LPO levels in serum by 31%, 41%, and 40% and in microsomes by 48%, 39%, and 35%, respectively. Vitamin E was protective in reducing the CCl(4)-induced increase in levels of AST, ALT, and gamma-glutamyl transferase as well as LPO. Furthermore, CCl(4) intoxication significantly (P < .05) decreased the activities of microsomal glucose-6-phosphatase, aniline hydroxylase, and cytosolic glutathione-S-transferase (GST). While pretreatments with KV, FI, and FII were able to ameliorate the levels of glucose-6-phosphatase and GST, there were no significant (P > .05) effects on the levels of aniline hydroxylase and DT-diaphorase. This study confirms that FI and FII from KV enhanced recovery from CCl(4)-induced hepatotoxicity by decreasing the extent of LPO and also inducing the levels of phase II enzyme (GST). These fractions are responsible for the observed antihepatotoxic effect of KV.
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PMID:Hepatoprotective activity of purified fractions from Garcinia kola seeds in mice intoxicated with carbon tetrachloride. 1880 Sep 5

Tienilic acid is reported to be converted into electrophilic metabolites by cytochrome P450 (CYP) in vitro. In vivo, however, the metabolites have not been detected and their effect on liver function is unknown. We previously demonstrated that tienilic acid decreased the GSH level and upregulated genes responsive to oxidative/electrophilic stresses, such as heme oxygenase-1 (Ho-1), glutamate-cysteine ligase modifier subunit (Gclm) and NAD(P)H dehydrogenase quinone 1 (Nqo1), in rat liver, as well as inducing hepatotoxicity by co-treatment with the glutathione biosynthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO). In this study, for the first time, we identified a glutathione-tienilic acid adduct, a stable conjugate of putative electrophilic metabolites with glutathione (GSH), in the bile of rats given a single oral dose of tienilic acid (300mg/kg). Furthermore, a tienilic acid-induced decrease in the GSH level and upregulation of Ho-1, Gclm and Nqo1 were completely blocked by pretreatment with the CYP inhibitor 1-aminobenzotriazole (ABT, 66mg/kg, i.p.). The increase in the serum ALT level and hepatocyte necrosis resulting from the combined dosing of BSO and tienilic acid was prevented by ABT, despite a low hepatic GSH level. These findings suggest that the electrophilic metabolites of tienilic acid produced by CYP induce electrophilic/oxidative stresses in the rat liver and this contributes to the hepatotoxicity of tienilic acid under impaired GSH biosynthesis.
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PMID:Involvement of cytochrome P450-mediated metabolism in tienilic acid hepatotoxicity in rats. 1899 96

Recent studies reported that 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors have pleotropic effects independent of their lipid-lowering properties. The present study was undertaken to determine whether treatment with rosuvastatin (RO) would be beneficial in a rat model of bile duct ligation (BDL). Animals were divided into three groups: a sham group (group I), a BDL group treated with vehicle (group II), and a BDL group treated with RO (10 mg/kg) (group III). Serum levels of total bilirubin, gamma-glutamyl transpeptidase, alanine aminotransferase, and aspartate aminotransferase decreased significantly in group III when compared to group II. Lipid peroxides and NO levels of group III were found to be significantly lower than those of group II. Antioxidant enzymes (superoxide dismutase, glutathione-S-transferase, and catalase) activity in liver tissues markedly decreased in group II, whereas treatment with RO preserved antioxidant enzyme activity. DT-diaphorase activity in group II was significantly higher than that in group III. The histopathological results showed multiple numbers of newly formed bile ductules with inflammatory cells infiltration in group II. These pathological changes were improved in group III. Our data indicate that RO ameliorates hepatic injury, inflammation, lipid peroxidation and increases antioxidant enzymes activity in rats subjected to BDL. RO may have a beneficial effect on treatment of cholestatic liver diseases.
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PMID:Effect of rosuvastatin on cholestasis-induced hepatic injury in rat livers. 2014 76


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