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

The microsomal ethanol oxidizing system comprises an ethanol-inducible cyto chrome P-4502E1, but the involvement of other P-450s has also been suggeste d. In our study, human CYP2E1, CYP1A2, and CYP3A4 were heterologously expre ssed in HepG2 cells, and their ethanol oxidation was assessed using a corre sponding selective inhibitor: all three P-450 isoenzymes metabolized ethano l. Selective inhibitors-4-methylpyrazole (CYP2E1), furafylline (CYP1A2), an d troleandomycin (CYP3A4)-also decreased microsomal ethanol oxidation in th e livers of 18 organ donors. The P-450-dependent ethanol oxidizing activiti es correlated significantly with those of the specific monooxygenases and t he 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 hig hest (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 t he major role. However, CYP1A2 and CYP3A4 contribute significantly to micro somal ethanol oxidation and may, therefore, also be involved in the pathoge nesis of alcoholic liver disease.