Abstract
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 theV max/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 (r 2 = 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.
Footnotes
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Send reprint requests to: Yoshihiko Funae, Ph.D., Labolatory of Chemistry, Osaka City University Medical School, 1–4-54 Asahi-machi, Abeno-ku, Osaka 545 Japan.
- Abbreviations:
- P450
- cytochrome P450
- SDS-PAGE
- sodium dodecyl sulfate polyacrylamide gel electrophoresis
- 3-MC
- 3-methylcholanthrene
- PB
- phenobarbital
- MAOS
- microsomal acetaldehyde-oxidizing system
- MEOS
- microsomal ethanol-oxidizing system
- DLPC
- dilauroylphosphatidylcholine
- ALDH
- acetaldehyde dehydrogenase
- Received July 2, 1996.
- Accepted October 1, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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