Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protective effects of alpha-Hederin on carbon tetrachloride-induced hepatotoxicities were investigated in mice. Pretreatment with alpha-Hederin prior to the administration of carbon tetrachloride significantly prevented the increase in serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activity and lipid peroxidation in a dose dependent manner. Hepatic glutathione levels and glutathione-S-transferase activities were not affected by pretreatment with alpha-Hederin alone but pretreatment with alpha-Hederin protects carbon tetrachloride-induced depletion of hepatic glutathione levels. The effects of alpha-Hederin on the cytochrome P450 (P450) 2E1, the major isozyme involved in carbon tetrachloride bioactivation were investigated. alpha-Hederin markedly decreased the P450 2E1-specific activities of p-nitrophenol and aniline hydroxylation in a dose-dependent manner. Consistent with these observations, the P450 2E1 expressions were also decreased, as determined by immunoblot analysis. These results demonstrate that treatment of mice with alpha-Hederin decreases the expression and activities of P450 2E1 enzyme, and reduces biotransformation of carbon tetrachloride, and diminished carbon tetrachloride-induced liver injury.
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PMID:The prevention of carbon tetrachloride-induced hepatotoxicity in mice by alpha-hederin: inhibiton of cytochrome P450 2E1 expression. 963 40

Precision-cut liver slices from phenobarbital-treated rats were incubated for up to 8 h with the industrial solvent and hepatotoxin bromobenzene at a final concentration of 1 mM. Phenobarbital pretreatment potentiates bromobenzene hepatotoxicity by inducing those P450 isoforms responsible for the formation of the active hepatotoxin, namely bromobenzene-3,4-oxide. A reduction in cell viability was indicated by a decrease in the K+, ATP and glutathione content of the slices and the increased release of the intracellular enzymes, lactate dehydrogenase and alanine aminotransferase, into the medium. Furthermore, levels of lipid peroxidation as judged by the formation of thiobarbituric acid reactive substances, were increased approximately 5-fold. Aged garlic extract (AGE) at concentrations of 1-5% (v/v) reduced the toxicity of bromobenzene in a concentration-dependent manner as judged by all of the parameters of viability studied, with the exception of lipid peroxidation which was reduced to control levels even at the lowest concentration of garlic extract used. AGE was found to cause partial inhibition of cytochrome P450 when assayed as both 7-ethoxycoumarin O-deethylase and 7-pentoxyresorufin O-depentylase activities, but even the highest concentration used inhibited both activities by less than 50%. It is suggested that the hepatoprotective effects of AGE are due primarily to the reduced glutathione-sparing properties of its constituents, most probably its organosulphur compounds.
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PMID:Protective effects of aged garlic extract against bromobenzene toxicity to precision cut rat liver slices. 967 69

2-(Allylthio)pyrazine (2-AP), synthesized for its possible use as a hepatoprotective agent, has been found to selectively inhibit rat hepatic cytochrome P450 2E1 (Kim et al., Biochem. Pharmacol., 53, 261-269, 1997), while it enhances the activities of phase II detoxification enzymes such as glutathione S-transferase and epoxide hydrolase. As part of a program in evaluating the chemopreventive potential of 2-AP, we have determined its effects on hepatotoxicity, mutagenicity and tumorigenicity of vinyl carbamate (VC), a prototypic hepatocarcinogen preferentially activated by P450 2E1 to the ultimate carcinogenic metabolite vinyl carbamate epoxide (VCO), which undergoes detoxification by glutathione conjugation and oxirane hydrolysis. Administration of 2-AP (100 mg/kg body wt) to male Sprague-Dawley rats by gavage, 2 days, 1 day and 4 h prior to VC or VCO, markedly ameliorated the hepatotoxicity of these compounds as determined by decreased serum aspartate aminotransferase and alanine aminotransferase activities. Furthermore, 2-AP pre-treatment significantly suppressed the VC-induced hepatocarcinogenesis in infant male B6C3F1 mice. In a separate experiment, the multiplicities of skin tumors formed in female ICR mice treated with 5.8 micromol of VC or VCO were inhibited 58 and 70%, respectively, by pre-treatment with 2-AP by oral administration. The mutational spectrum of ras-oncogene in papillomas was not altered by 2-AP pre-treatment. 2-AP also inhibited the mutagenicity of VC in the Salmonella-microsome assay. Taken together, these findings suggest that 2-AP is a potential chemopreventive agent.
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PMID:Chemopreventive effects of 2-(allylthio)pyrazine on hepatic lesion, mutagenesis and tumorigenesis induced by vinyl carbamate or vinyl carbamate epoxide. 968 87

Acetaminophen (APAP) is known to cause centrilobular hepatic necrosis under overdose conditions. This is thought to be mediated via the P450-generated reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI). Initially, NAPQI is detoxified by conjugation with glutathione (GSH), but once GSH is depleted, NAPQI reacts more extensively with hepatic proteins leading to hepatocellular damage. The P450 isoforms thought to be responsible for APAP hepatotoxicity in humans are CYP2E1, CYP1A2, and CYP3A4, and thus, we have investigated the effect of murine Cyp1a2 on APAP hepatotoxicity using Cyp1a2 knockout mice (Liang et al., Proc. Natl. Acad. Sci. USA 93, 1671-1676, 1996). Doses of 250 mg/kg were markedly hepatotoxic in these mice, and surprisingly, deaths only occurred in the knock-out and heterozygote mice over a 24-h period after dosing. Furthermore, there were no significant differences among survivors of any genotype in serum ALT concentrations, a well correlated indicator of APAP hepatotoxicity in mice. Finally, no differences were observed in the urinary metabolites excreted ove the 24-h period, including those derived from GSH conjugation of the major reactive metabolite NAPQI. Consistent with the effects on hepatotoxicity and metabolism, 2 h after hepatotoxic doses (500 mg/kg, i.p.) of APAP no significant differences were observed in total whole liver homogenate nonprotein thiol concentrations among the three genotypes even though hepatic thiols were decreased compared to control animals (> 90%). In addition, when the liver cytosol and microsome samples were examined by immunoblotting for the presence of APAP-protein adducts using a specific antiserum, there were no observable differences in either the intensity of staining or in the spectrum of adducts formed between APAP-dosed mice of any genotype. The cumulative data suggest that Cyp1a2 doses not play a significant role in APAP hepatotoxicity in these mice.
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PMID:Role of CYP1A2 in the hepatotoxicity of acetaminophen: investigations using Cyp1a2 null mice. 987 4

2-(Allylthio)pyrazine (2-AP), a synthetic organosulfur compound, exhibits hepatoprotective and chemopreventive effects. The effects of 2-AP on aflatoxin B1 (AFB1)-induced hepatotoxicity was studied in rats. 2-AP treatment substantially reduced AFB1-induced toxicity, as evidenced by reduction in the mortality rate of animals as well as decreases in serum alanine aminotransferase and sorbitol dehydrogenase activities. AFB -induced lipid peroxidation was also significantly reduced in rats by 2-AP treatment. Studies were extended to determine whether 2-AP was active in inhibiting cytochrome P450-mediated metabolic activation of AFB1. Covalent binding of AFB1 to calf thymus DNA in the presence of S-9 fraction was inhibited by 2-AP in vitro. Hepatic microsomal pentoxyresorufin-O-depentylase and ethoxyresorufin-O-deethylase activities were also potently inhibited by 2-AP. These results demonstrated that 2-AP was effective in protecting the liver against AFB1-induced toxicity and the mechanism of chemoprotection by 2-AP might involve inhibition of the P450 2B- and 3A2-mediated metabolism of AFB1.
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PMID:2-(allylthio)pyrazine inhibition of aflatoxin B1-induced hepatotoxicity in rats: inhibition of cytochrome P450 2B- and 3A2-mediated bioactivation. 992 Mar 47

A possible role of metabolic activation by cytochrome P450 (P450) in thioacetamide-induced hepatotoxicity was investigated in male BALB/c mice. The mice were pretreated with the P450 inducer, beta-ionone, subcutaneously at 600 mg/kg, 72 and 48 h prior to an intraperitoneal administration of either 100 or 200 mg/kg of thioacetamide. The elevated activities of serum alanine aminotransferase and serum aspartate aminotransferase by thioacetamide were greatly potentiated by the pretreatment with beta-ionone. Moreover, the potentiation of thioacetamide-induced hepatotoxicity was also observed in the histopathological examination of livers. The hepatic necrosis by thioacetamide was potentiated when mice were pretreated with beta-ionone. In liver microsomes, the activities of P450 2B-specific pentoxyresorufin O-depentylase and benzyloxyresorufin O-debenzylase were significantly induced by the treatment with beta-ionone. Beta-ionone also induced other P450-associated monooxygenases. Because the pretreatment with beta-ionone was not hepatotoxic at the dose inducing P450s. our present results suggest that beta-ionone may be a useful model inducer of P450 enzyme(s) in studying toxic mechanism of certain chemicals which require metabolic activation by P450s in mice.
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PMID:Pretreatment of male BALB/c mice with beta-ionone potentiates thioacetamide-induced hepatotoxicity. 1009 55

Thioureas have been employed as potent hydroxyl radical scavengers and also inhibit production of oxygen free radicals. The in vitro oxygen radical scavenging effect by N,N'-substituted thioureas including dimethylthiourea (DMT), diethylthiourea (DET), tetramethylthiourea (TMT) and diphenylthiourea (DPT) was assessed by the conversion of phi x-174 DNA from supercoiled DNA to the open circular form or to fragmented DNA. Addition of the N,N'-substituted thioureas to the incubation mixture significantly prevented a single strand breakage of phi x-174 DNA induced by autooxidation of benzenetriol. These thioureas were also effective in preventing degradation of phi x-174 DNA induced by autooxidation of benzenetriol in the presence of ferrous iron. In view of the in vitro radical scavenging effect by the thioureas and the role of reactive oxygen species in the induction of phase II detoxifying enzymes, expression of microsomal epoxide hydrolase (mEH) and rGSTA2 in response to these agents was investigated in the rat liver. Rats treated with each of the alkylthioureas exhibited marked increases of mEH and rGSTA2 mRNA levels with TMT being the most effective. DPT an arylthiourea, however, was minimally active in increasing the mRNAs. Time-course studies revealed that DMT, DET and TMT increased the mRNA levels to the greatest extent at 24 h after a single dose of treatment. The levels of mEH and rGSTA2 mRNA were elevated in a dose-dependent manner by the alkylthioureas. Immunoblot analysis showed that the alkylthioureas induced mEH and rGSTA2 proteins in the liver (0.6 mmol/kg per day, 3 days), which was consistent with the increases in the mRNA levels. DMT, DET or TMT enhanced CCl4-induced liver toxicity, as monitored by plasma aminotransferase activity, although each of the agents alone caused only slight increase in the alanine aminotransferase activity. In contrast to the effects of the alkylthioureas, DPT protected the liver against the toxicant-induced injury. All of the thioureas prevented decreases in the hepatic glutathione level by CCl4. Expression of cytochrome P450 2E1 and P450 2B1/2, which are implicated with metabolic activation of CCl4, was assessed after treatment with the thioureas. P450 2E1 and P450 2B1/2 were differentially induced by the alkylthioureas with the expression of P450 2E1 being inversely related with that of P450 2B1/2. These results showed that N,N'-substituted alkylthioureas were capable of inducing mEH and rGSTA2 in the liver with elevation of the mRNAs, that induction of mEH and rGSTA2 by these alkylthioureas might be mediated by production of the reactive oxygens derived from metabolic activation of the agents irrespective of their radical scavenging effect and that the agents rather enhanced toxicant-induced liver injury with the induction of P450 2E1 or P450 2B1/2.
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PMID:Thioureas differentially induce rat hepatic microsomal epoxide hydrolase and rGSTA2 irrespective of their oxygen radical scavenging effect: effects on toxicant-induced liver injury. 1019 May 72

The protective effects of oleanolic acid on carbon tetrachloride-induced hepatotoxicities and the possible mechanisms involved in this protection were investigated in mice. Pretreatment with oleanolic acid prior to the administration of carbon tetrachloride significantly prevented the increase in serum alanine aminotransferase and lactate dehydrogenase activity and liver lipid peroxidation in a dose-dependent manner. Hepatic glutathione levels and glutathione-S-transferase activities were not affected by treatment with oleanolic acid alone but pretreatment with oleanolic acid protects carbon tetrachloride-induced depletion of hepatic glutathione levels. The effects of oleanolic acid on the cytochrome P450 (P450) 2E1, the major isozyme involved in carbon tetrachloride bioactivation were investigated. Treatment of mice with oleanolic acid resulted in a significant decrease of P450 2E1-dependent p-nitrophenol and aniline hydroxylation in a dose-dependent manner. Consistent with these observations, the P450 2E1 expressions were also decreased, as determined by immunoblot analysis. These results show that the protective effects of oleanolic acid against the carbon tetrachloride-induced hepatotoxicity may, at least in part, be due to its ability to block bioactivation of carbon tetrachloride mainly by the inhibition of expression and activities of P450 2E1.
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PMID:Inhibition of cytochrome P450 2E1 expression by oleanolic acid: hepatoprotective effects against carbon tetrachloride-induced hepatic injury. 1035 42

Effects of thioacetamide on antibody response to sheep red blood cells were investigated in male BALB/c mice. When mice were treated intraperitoneally with thioacetamide once, the antibody response was significantly suppressed at 200 mg/kg with hepatotoxicity. When mice were treated intraperitoneally with thioacetamide for 7 consecutive days, the antibody response was suppressed at 50 mg/kg without hepatotoxicity. To determine the possible role of metabolic activation by cytochrome P450 in thioacetamide-induced suppression of antibody response, mice were pretreated with phenobarbital intraperitoneally for 3 days, followed by intraperitoneal administration of 100 mg/kg of thioacetamide for 3 days. The elevated activities of serum aspartate aminotransferase and alanine aminotransferase by thioacetamide were potentiated by phenobarbital pretreatment. The suppression of antibody response by thioacetamide was potentiated by phenobarbital. In liver microsomes, the activities of P450 2B-specific enzymes were induced by phenobarbital. Our present results suggest that thioacetamide may require metabolic activation by P450 to its immunosuppressive form(s).
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PMID:Role of metabolic activation by cytochrome P450 in thioacetamide-induced suppression of antibody response in male BALB/c mice. 1071 88

In mice depleted of GSH by treatment with buthionine sulfoximine (BSO), methimazole (2-mercapto-1-methylimidazole, MMI) causes liver injury characterized by centrilobular necrosis of hepatocytes and an increase in serum alanine transaminase (SALT) activity. MMI requires metabolic activation by both P450 monooxygenase and flavin-containing monooxygenase (FMO) before it produces the hepatotoxicity. MMI and its analogues were examined for the ability to increase SALT activity in GSH-depleted mice. Saturation of the C-4,5 double bond in MMI resulted in a complete loss of hepatotoxicity. Similarly, ring fusion of a benzene nucleus to the C-4,5 double bond, forming 2-mercapto-1-methylbenzimidazole, abolished the toxic potency. As for MMI, 2-mercapto-1,4,5-trimethylimidazole, and 2-mercapto-1-methyl-4, 5-di-n-propylimidazole, the toxic potency decreased with the increasing bulk of the 4- and 5-alkyl substituents. Furthermore, methylation of the thiol group of MMI totally reduced its toxicity. These structural requirements and the known toxicity of thiono-sulfur compounds led us to the hypothesis that MMI would undergo epoxidation of the C-4,5 double bond by P450 enzymes and, after being hydrolyzed, the resulting epoxide would be then decomposed to form N-methylthiourea, a proximate toxicant. Before N-methylthiourea would produce toxicity, it would be further biotransformed to its S-oxidized metabolites mainly by FMO. Evidence for this hypothesis was provided by the facts that N-methylthiourea and glyoxal as the accompanying fragment were identified as urinary metabolites in mice treated with MMI and that N-methylthiourea caused a marked increase in SALT activity when administered to mice in combination with BSO.
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PMID:Evidence for the involvement of N-methylthiourea, a ring cleavage metabolite, in the hepatotoxicity of methimazole in glutathione-depleted mice: structure-toxicity and metabolic studies. 1072 13


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