Respective roles of human cytochrome P-4502E1, 1A2, and 3A4 in the hepatic microsomal ethanol oxidizing system

The microsomal ethanol oxidizing system comprises an ethanol-inducible cytochrome P-4502E1, but the involvement of other P-450s has also been suggested. In our study, human CYP2E1, CYP1A2, and CYP3A4 were heterologously expressed in HepG2 cells, and their ethanol oxidation was assessed using a corre...

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Published in:Alcoholism, clinical and experimental research clinical and experimental research, 1998-12, Vol.22 (9), p.2125-2132
Main Authors: SALMELA, K. S, KESSOVA, I. G, TSYRLOV, I. B, LIEBER, C. S
Format: Article
Language:English
Subjects:
Adolescent
Adult
Alcoholism and acute alcohol poisoning
Biological and medical sciences
Cell Line
Child
Child, Preschool
Cytochrome P-450 CYP1A2 - physiology
Cytochrome P-450 CYP2E1 - physiology
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System - physiology
Ethanol - pharmacokinetics
Female
Humans
Liver Diseases, Alcoholic - enzymology
Male
Medical sciences
Microsomes, Liver - enzymology
Mixed Function Oxygenases - physiology
Toxicology
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Summary:The microsomal ethanol oxidizing system comprises an ethanol-inducible cytochrome P-4502E1, but the involvement of other P-450s has also been suggested. In our study, human CYP2E1, CYP1A2, and CYP3A4 were heterologously expressed in HepG2 cells, and their ethanol oxidation was assessed using a corresponding selective inhibitor: all three P-450 isoenzymes metabolized ethanol. Selective inhibitors-4-methylpyrazole (CYP2E1), furafylline (CYP1A2), and troleandomycin (CYP3A4)-also decreased microsomal ethanol oxidation in the livers of 18 organ donors. The P-450-dependent ethanol oxidizing activities correlated significantly with those of the specific monooxygenases and the immunochemically determined microsomal content of the respective P-450. The mean CYP2E1-dependent ethanol oxidation in human liver microsomes [1.41+/-0.11 nmol min(-1) (mg protein)(-1)] was twice that of CYP1A2 (0.61+/-0.07) or CYP3A4 (0.73+/-0.11) (p < 0.05). Furthermore, CYP2E1 had the highest (p < 0.05) specific activity [28+/-2 nmol min(-1) (nmol CYP2E1)(-1) versus 17+/-3 nmol min(-1) (nmol CYP1A2)(-1), and 12+/-2 nmol min(-1) (CYP3A4)(-1), respectively]. Thus, in human liver microsomes, CYP2E1 plays the major role. However, CYP1A2 and CYP3A4 contribute significantly to microsomal ethanol oxidation and may, therefore, also be involved in the pathogenesis of alcoholic liver disease.
ISSN:0145-6008
1530-0277
DOI:10.1097/00000374-199812000-00033