Acetaldehyde as well as ethanol is metabolized by human CYP2E1.
Acetaldehyde was oxidized by rat and human hepatic microsomes in the presence of NADPH. We designated this NADPH-dependent oxidation system MAOS (microsomal acetaldehyde-oxidizing system), to distinguish it from the NAD-dependent acetaldehyde oxidation system of acetaldehyde dehydrogenase in mitochondria and cytosol. This activity was increased 2.3-fold by giving rats ethanol. Judging from the Vmax/Km values, the metabolic capacity of rat hepatic microsomes for MAOS activity was increased 24-fold by ethanol. The acetaldehyde oxidation activity of eight forms of purified rat cytochrome P450 was investigated in a reconstituted system. CYP2E1 had the highest level, followed by CYP1A2 and 4A2. Immunoinhibition studies showed that an anti-CYP2E1 antibody inhibited 90% of the MAOS activity in rats given ethanol. NADPH-dependent acetate formation was 12% or 33.6% of the NAD-dependent acetate formation in liver homogenates of control rats and those treated with ethanol, respectively. We investigated human MAOS activity further. Among the 10 forms of human cytochrome P450 expressed in yeast, CYP2E1 had especially high acetaldehyde oxidation activity. The correlation of MAOS activity with the levels of immunoreactive CYP2E1 in individual human microsomes was highly significant (r2 = 0.88, P < .01). These results indicate that hepatic CYP2E1 mainly contributes to MAOS in rats and humans, the pathway of which may play an alternative role against acetaldehyde in the liver after alcohol consumption together with acetaldehyde dehydrogenase in the metabolism of acetaldehyde.
Kunitoh
S
S
Department of Public Health, Osaka City University Medical School, Abeno-ku, Japan.
Imaoka
S
S
Hiroi
T
T
Yabusaki
Y
Y
Monna
T
T
Funae
Y
Y
D000079:Acetaldehyde / Q000378:metabolism*; D000328:Adult; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology; D003001:Cloning, Molecular; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism*; D005260:Female; D006801:Humans; D007700:Kinetics; D008113:Liver Neoplasms / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D012044:Regression Analysis; D012441:Saccharomyces cerevisiae; D013379:Substrate Specificity
D011994:Recombinant Proteins; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D000079:Acetaldehyde