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)

Intraperitoneal administration of acorn extract of dosage levels of 200, 400 and 600 mg/kg body weight did not produce significant change in the hepatic microsomal cytochrome P-450 levels and the activities of NADPH-cytochrome c reductase, benzphetamine N-demethylase and aniline hydroxylase in young, adult rats (weighing 200-250 g), with the exception of the activity of benzphetamine N-demethylase at the 600 mg/kg dose which was decreased significantly. On the other hand, a dose of only 100 mg/kg body weight ip to old rats (weighing 400-450 g) caused significant decreases in the microsomal cytochrome P-450, benzphetamine N-demethylase and NADPH-cytochrome c reductase activities. However, there was no significant change in the activity of aniline hydroxylase in these rats, indicating selective inhibition of the microsomal enzymes and higher susceptibility of old rats than young ones to acorn toxicants. When the serum samples from the treated young rats were analyzed for sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities as markers of liver toxicity, these activities were significantly higher in the treated rats than the corresponding control values. Similar changes were noted for old rats receiving a dose of 100 mg/kg body weight of acorn extract. The results indicate that acorn extract affects old rats more than young rats as measured by its effect on liver and liver microsomal enzymes.
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PMID:Age-dependent toxicity of acorn extract in young and old male rats. 230 Nov 45

Cocaine may be metabolized either by ester hydrolysis to inactive products or by oxidation via a cytochrome P-450 and FAD-monooxygenase pathway to a hepatotoxic metabolite, presumably norcocaine nitroxide. Mice are the species most susceptible to cocaine-induced hepatotoxicity (CIH), and marked strain differences in response have been found. Female mice are very resistant to CIH, whereas males are susceptible, indicating that hormonal factors may be involved. We treated mice of 5 inbred strains with cocaine at three ages: 20 days (weanling), 30 days (adolescent) and 60 days (adult). The CIH response was assessed by measurement of plasma alanine aminotransferase (ALT) activity 18 hours later. For each of the strains females of all three age groups were resistant to CIH, and males did not begin to develop CIH until approximately 30 days of age. The degree of CIH in 30-day-old males was intermediate between the levels found in 20-day-old males and adult males. These data suggest that the enzyme, or enzymes, responsible for the production of the toxic metabolite are absent, or at very low levels, in female and immature male mice, and that they are either inducible by androgens or are repressed by estrogens or progestins. It is possible that these enzymes may be involved in the production of toxic metabolites of compounds other than cocaine.
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PMID:Developmental expression of cocaine hepatotoxicity in the mouse. 235 6

Isoniazid (INH) is a selective inducer of cytochrome P-450 isozymes that are involved in the biotransformation of organohalogen anesthetics. It has been used to produce a rat model of halothane-associated hepatotoxicity that was linked to enhanced oxidative biotransformation of the anesthetic. Guinea pigs were pretreated with INH in order to potentiate halothane-induced hepatic necrosis and to study the oxidative pathway as a hepatotoxic mechanism in this species. The animals received either 12.5, 25.0 or 50.0 mg kg-1 INH i.p. for 7 days. Following halothane exposure, there were dose-dependent increases in plasma levels of the oxidative halothane metabolite, trifluoroacetic acid. These increases were associated with increases in 48 h plasma alanine aminotransferase (ALT) levels. When combined with halothane exposure, the two higher doses of INH killed the animals before planned termination. These deaths were not attributable to hepatic failure. Dividing the 25 mg kg-1 INH dose into twice daily injections of 12.5 mg kg-1 reduced deaths. INH pretreatment control animals exhibited occasional non-dose-dependent increases in ALT as well as the occurrence of fatty vacuolization of hepatocytes at the highest dose. Even though INH pretreatment enhanced oxidative halothane biotransformation and subsequent hepatotoxicity, sensitivity of guinea pigs to the deleterious actions of INH would contraindicate its use as a cytochrome P-450 induction agent.
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PMID:Isoniazid potentiation of a guinea pig model of halothane-associated hepatotoxicity. 238 Apr 77

The hepatonecrogenic properties of chloroform (CHCl3) can be modified by the administration of various chemicals. The ability of methyl isobutyl ketone (MIBK) and its two major metabolites, 4-methyl-2-pentanol (4MPOL) and 4-hydroxymethyl isobutyl ketone (4-OHMIBK) to potentiate the liver injury induced by CHCl3 was assessed in rats. The parent compound and both metabolites significantly increased the liver damage induced by CHCl3, as demonstrated by the elevation of the plasma activity of two transferases alanine aminotransferase and ornithine carbamoyl transferase and by the severity of the morphological changes. Moreover, the minimally effective dosage needed to potentiate CHCl3-induced hepatotoxicity was approximately 5 mmol/kg for the three compounds. We also studied the inducing properties of MIBK (cytochrome P-450 liver content and the activity of aniline hydroxylase, 7-ethoxycoumarin O-deethylase, and aminopyrine N-demethylase). Cytochrome P-450 content and the oxidation of aniline and 7-ethoxycoumarin were significantly increased with either a single (7.5 mmol/kg or greater) or a multiple (5.0 and 7.5 mmol.kg-1.day-1 for 5 days) administration of MIBK. An increase in the activity of the aminopyrine demethylase was also elicited by the repetitive administration of MIBK. With gel electrophoresis, we found that MIBK significantly increased the 52.1- and 54.1-kDa proteins, corresponding most probably to P-450 isozymes.
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PMID:Potentiation of chloroform-induced hepatotoxicity by methyl isobutyl ketone and two metabolites. 239 Jul 35

Female Sprague-Dawley rats were given 0, 168, 840, 2550 or 4200 mg/kg of 1,4-dioxane 21 and 4 h before sacrifice. Hepatic DNA damage (by the alkaline elution technique), ornithine decarboxylase activity (ODC), reduced glutathione content, cytochrome P-450 content and serum alanine aminotransferase activity (ALT) were determined. Treatment with 1,4-dioxane increased hepatic DNA damage and cytochrome P-450 content at doses of 2550 and 4200 mg/kg. Large increases in the activity of hepatic ODC were observed at 840, 2550 and 4200 mg/kg of 1,4-dioxane. Thus the data suggest that 1,4-dioxane is a weak genotoxic carcinogen in addition to being a strong promoter of carcinogenesis (a non-genotoxic carcinogen).
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PMID:Is 1,4-dioxane a genotoxic carcinogen? 239 85

Exposure to chlordecone (CD, Kepone) is known to increase the hepatotoxicity of chloroform (CHCl3) in rats. A time-course analysis was conducted relating several indices of biotransformation capacity with the ability of CD to potentiate CHCl3-induced hepatotoxicity. Male Sprague-Dawley rats were given a single administration of corn oil alone or CD (50 mg/kg, po) dissolved in corn oil. At 2, 4, 8, 16, 20, 24, or 32 days posttreatment, groups of rats were killed and their livers were analyzed for (i) cytochrome P-450, NADPH-dependent cytochrome c reductase, cytochrome b5 and glutathione content or (ii) in vitro irreversible binding of 14CHCl3-derived radiolabel to microsomal protein. Similarly treated rats were challenged (2-32 days posttreatment) with CHCl3 (0.5 mL/kg po); 24 h later, liver damage was assessed by plasma alanine aminotransferase (ALT), plasma ornithine carbamyl transferase (OCT), plasma bilirubin, and hepatic glucose-6-phosphatase. CD potentiation was maximal 2 days posttreatment; and enhanced susceptibility to CHCl3 persisted up to 20-24 days post-CD treatment. In a parallel study animals treated with chlordecone were killed 8, 16, 20, 24, or 32 days later. Blood, kidney, liver, and adipose tissue samples were taken and analyzed for chlordecone content. The results suggest that a general temporal correlation exists between biotransformation rate (microsomal 14C binding), chlordecone content, and the severity of liver injury; the other parameters monitored do not appear to relate directly to the potentiation.
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PMID:Temporal relationships between biotransformation, detoxication, and chlordecone potentiation of chloroform-induced hepatotoxicity. 242 14

Models of hepatic intraacinar zonation have been proposed previously; in most models, direct visualization of the acinar destruction is not possible while intact hepatocyte recovery-viability often presents a problem for subsequent metabolic studies. In the present studies, the liver is isolated in situ and perfused with Krebs-Henseleit buffer, pH 7.4. A 1.5-mL intrahepatic volume of a 7 mM digitonin solution is then injected at a flow rate of 6 mL/min for 15 s via the portal vein or via the vena cava for selective destruction of the periportal (PP) or perivenous (PV) region of the acinus. To avoid diffusion of the detergent throughout the acinus, the liver is then immediately perfused with oxygenated Hanks buffer in the direction opposite to that of digitonin injection. The preparation can then be used for histological evaluation, for studies on isolated-perfused liver, or for isolation of hepatocytes. Direct visualization of the acinar destruction can be achieved by coloring the permeabilized cells with 0.2 mM trypan blue; the liver is then fixed in situ by a 10-min perfusion with paraformaldehyde and histological evaluation is achieved by eosine staining of liver slices. Following isolation of hepatocytes by collagenase perfusion, a highly significant PV localization was found for the synthesis of glutamine, the N-demethylation of aminopyrine, and the glucuronidation of p-nitrophenol, whereas a highly significant PP zonation was found for alanine aminotransferase. By contrast, no specific acinar zonation was found for the enzymes 7-ethoxycoumarin O-deethylase and aniline p-hydroxylase. Total cytochrome P-450 was 0.42 +/- 0.006 and 0.4 +/- 0.03 nmol/10(6) hepatocytes in PV and PP, respectively (nonsignificant).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hepatic zonation of drug metabolizing enzymes. Studies on hepatocytes isolated from the periportal or perivenous region of the liver acinus. 251 8

The increase in serum gamma-glutamyl transpeptidase (GGT) is a well known marker of chronic alcoholism in man. We have previously shown that ethanol (180 mM) induces GGT activity 2-3-fold in the C2 rat hepatoma cell line. In this study, we have analyzed the interaction of ethanol with steroid hormones and drugs in this well defined cell culture system. Dexamethasone (100 nM), a synthetic glucocorticoid agonist, completely prevented the induction of GGT by ethanol, but had no effect when added alone. This inhibitory effect was also observed with other corticosteroids, but not with sex steroids; it was prevented by RU 486, a glucocorticoid antagonist. These observations suggest that dexamethasone acts through a high affinity glucocorticoid receptor. Conversely, ethanol did not interfere with the glucocorticoid induction of alanine aminotransferase in the same cell. We have analyzed the metabolism of ethanol in the C2 cells. These cells lack significant alcohol dehydrogenase activity as well as any cytochrome P-450 Alc immunoreactivity. Dexamethasone did not modify the disappearance of ethanol in the culture medium of those cells. We conclude that glucocorticoid hormones interact with ethanol at the cellular level, and that this interaction does not involve a modification of alcohol metabolism.
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PMID:Glucocorticoid hormones prevent the induction of gamma-glutamyl transpeptidase by ethanol in a rat hepatoma cell line. 256 56

Three chlorinated methanes, carbon tetrachloride, chloroform, and methylene chloride, known to cause liver tumors in rodents, were given by oral gavage to adult female rats both 21 h and 4 h before sacrifice. Then hepatic DNA damage, ornithine decarboxylase (ODC), cytochrome P-450, glutathione content, and serum alanine aminotransferase (SGPT) activity assays were performed. Carbon tetrachloride increased rat hepatic ODC activity and decreased cytochrome P-450 content at doses both below and above cytotoxicity (as measured by increased SGPT activity). At 54 and 160 mg/kg, chloroform increased hepatic ODC activity with minimal or no elevation in SGPT activity. At 480 mg/kg chloroform increased hepatic ODC and SGPT activity. A dose of 1,275 mg/kg methylene chloride caused a small, but significant amount of hepatic DNA damage. When these three compounds are compared on either an equimolar or equitoxic (1/5 LD50) basis, their ability to induce hepatic ODC or increase SGPT activity was carbon tetrachloride greater than chloroform greater than methylene chloride. The results of this biochemical study are interpreted with respect to the ability of chemicals to cause hepatic cancer by either genetic or epigenetic mechanisms.
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PMID:Biochemical effects of three carcinogenic chlorinated methanes in rat liver. 256 70

Changes in body weight gain and in biochemical parameters of blood and liver were assessed in Sprague-Dawley rats after multiple oral administration of three test doses of an Alberta crude oil (ACO). Rats treated with ACO (1.25-5 ml/kg) did not show statistically significant (p greater than .05) differences from control, corn-oil treated (5 ml/kg) rats, in body weight gains, liver weight, and blood biochemical indicators of liver (alanine aminotransferase, gamma glutamyltransferase), kidney (blood urea nitrogen, creatinine), and erythrocyte (adenosine 5'-triphosphate, 2,3-diphosphoglyceric acid, reduced glutathione) cytotoxicity. Treatment with ACO, however, caused statistically significant (p less than .05) and dose-related increases from control in (1) microsomal protein and cytochrome P-450 content, and NADPH-cytochrome c reductase, aryl hydrocarbon hydroxylase (AHH), and 7-ethoxycoumarin-O-deethylase (7-ECOD) activities, and (2) cytosolic glutathione transferase activity of liver. The induction of hepatic cytochrome P-450 and xenobiotic-metabolizing enzymes in microsomes of ACO-treated rats was probably associated with dose-related changes in isozymic forms of cytochrome P-450, as evidenced by (1) appearance of a 448-nm spectral peak in microsomes of ACO-treated rats and (2) differences in the inhibition pattern of AHH and 7-ECOD activities in microsomes of control and ACO-treated rats upon treatment with metyrapone and 7,8-benzoflavone.
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PMID:Induction of hepatic cytochrome P-450 and xenobiotic metabolizing enzymes in rats gavaged with an Alberta crude oil. 257 35


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