Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q6LER5 (cytochrome P450IIE1)
 63 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The liver enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are responsible for the oxidative metabolism of ethanol, are polymorphic in humans. Cytochrome P450IIE1, an ethanol-inducible isozyme of liver microsomal P450, is also important in ethanol metabolism. Genetic polymorphisms in the 5'-flanking region of the human cytochrome P450IIE1 gene have recently been reported. We hypothesized that the polymorphisms of ADH, ALDH, and P450IIE1 modify the susceptibility to development of alcoholism. We determined the genotypes of the ADH2, ALDH2, and P450IIE1 loci of 96 Japanese alcoholics and 60 healthy male subjects, using leukocyte DNA by the restriction fragment-length polymorphism by polymerase chain reaction. The alcoholics had significantly higher frequencies of the ADH2(1) and ALDH2(1) alleles than did the healthy subjects. No significant difference in the frequency of the P450IIE1 genotype was observed between the alcoholics and the healthy subjects. In conclusion, genetic polymorphisms of the ADH and ALDH genes, but not of the P450IIE1 gene, influence the risk of developing alcoholism in Japanese.
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PMID:Alcohol-metabolizing enzyme polymorphisms and alcoholism in Japan. 748 44

Groups of male and female F-344 rats and B6C3F1 mice were exposed to 15,000 ppm ethyl chloride (monochloroethane, ECL) or to air for 5 days (6 h/day). In this report, features of the P450-dependent ECL metabolism in the animals are described. A concurrent report describes the in vitro and in vivo features of the GSH-dependent ECL metabolism (Fedtke et al. 1994). ECL is oxidatively dechlorinated in an NADPH- and O2-dependent reaction, resulting in the formation of acetaldehyde (AC). The oxidative ECL metabolism rates in microsomal incubations were measured. The results indicated induction of the oxidative ECL metabolism by ECL itself in mice and female rats. The hydroxylation of p-nitrophenol, which was used as an indicator of P450IIE1 activity, was also induced in microsomal incubations from ECL-exposed mice and female rats, but, corresponding to the ECL metabolism, not in male rats. In contrast, catalytic activities related to P450IA and IIB subfamilies were not induced by ECL treatment. Additional experiments with the P450IIE1-specific inhibitor 3-amino-1,2,4-triazole and induction experiments with acetone, phenobarbital and methylcholanthrene confirmed that the isoenzyme mainly involved in the dechlorination reaction is cytochrome P450IIE1. AC was not detected in serum of ECL exposed animals and only slightly enhanced amounts were detected in urine samples from ECL exposed mice, reflecting the high capacities of the AC metabolizing pathways in vivo. The data are discussed with regard to the results of a 2-year bioassay with F-344 rats and B6C3F1 mice exposed to 15,000 ppm ECL (NTP 1989a).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Species differences in the biotransformation of ethyl chloride. I. Cytochrome P450-dependent metabolism. 802 62

The study describes the kinetics of demethylation of mononitrosocaffeidine (MNC), a new asymmetric N-nitrosamine derived from caffeine. The demethylation of its precursor compound caffeidine was also studied. The results presented here suggest (a) that liver microsomes from fasted rats preferentially demethylate the N-methylnitrosamine group in MNC indicating the demethylation by cytochrome P450IIE1, (b) demethylation of MNC shows two apparent Km values, one of 117-166 microM responsible for the demethylation at the N-methylnitrosamino group of MNC, and the other Km of 1.84-2.26 mM for the remaining N-demethylations, (c) in contrast, caffeidine is a low affinity substrate for microsomal demethylation as indicated by a high Km of 14.3-16.3 mM, and (d) the demethylation at amino-N amino-N, and N-1 in both these compounds are mainly catalysed by P450 enzymes induced by Aroclor 1245 in rats.
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PMID:Caffeine-derived N-nitroso compounds. IV: Kinetics of mononitrosocaffeidine demethylation by rat liver microsomes. 818 50

1,1,1-Trichloroethane (TRI) is a widely used solvent that has become a frequent contaminant of drinking water supplies in the U.S. There is very little information available on the potential for oral TRI to damage the liver or to alter its P450 metabolic capacity. Thus, a major objective of this investigation was to assess the acute, short-term, and subchronic hepatotoxicity of oral TRI. In the acute study, male Sprague-Dawley (S-D) rats were gavaged with 0, 0.5, 1, 2, or 4 g TRI/kg bw and killed 24 h later. No acute effects were apparent other than CNS depression. Other male S-D rats received 0, 0.5, 5, or 10 g TRI/kg po once daily for 5 consecutive days, rested for 2 days, and were dosed for 4 additional days. Groups of the animals were sacrificed for evaluation of hepatotoxicity 1, 5, and 12 days after initiation of the short-term experiment. This dosage regimen caused numerous fatalities at 5 and 10 g/kg, but no increases in serum enzymes or histopathological changes in the liver. For the subchronic study, male S-D rats were gavaged 5 times weekly with 0, 0.5, 2.5, or 5.0 g TRI/kg for 50 days. The 0 and 0.5 g/kg groups were dosed for 13 weeks. A substantial number of rats receiving 2.5 and 5.0 g/kg died, apparently due to effects of repeated, protracted CNS depression. There was evidence of slight hepatocytotoxicity at 10 g/kg, but no progression of injury nor appearance of adverse effects were seen during acute or short-term exposure. Ingestion of 0.5 g/kg over 13 weeks did not cause apparent CNS depression, body or organ weight changes, clinical chemistry abnormalities, histopathological changes in the liver, or fatalities. Additional experiments did reveal that 0.5 g/kg and higher doses induced hepatic microsomal cytochrome P450IIE1 (CYP2E1) in a dose- and time-dependent manner. Induction of CYP2E1 activity occurred sooner, but was of shorter duration than CYP2B1/2 induction. CYP1A1 activity was not enhanced. In summary, 0.5 g/kg po was the acute, short-term, and subchronic NOAEL for TRI, for effects other than transient CYP2E1 induction, under the conditions of this investigation. Oral TRI appears to have very limited capacity to induce P450s or to cause liver injury in male S-D rats, even when administered repeatedly by gavage in near-lethal or lethal dosages under conditions intended to maximize hepatic effects.
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PMID:Acute, short-term, and subchronic oral toxicity of 1,1,1-trichloroethane in rats. 1124 49


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