Antipyrine and aminopyrine induce acetaldehyde accumulation from ethanol in isolated hepatocytes.
The addition of antipyrine or aminopyrine to isolated hepatocytes derived from normal rats and incubated with ethanol caused a significant decrease in the oxidation of ethanol to acetate. This decrease was associated with a corresponding accumulation of acetaldehyde. The degree of inhibition with each drug was concentration-dependent, and there was a lag phase before inhibition of acetate formation and acetaldehyde accumulation became apparent. These effects were augmented in cells isolated from phenobarbital-treated rats, and the lag phase was reduced, implying that the effects of both drugs were dependent on their cytochrome P-450-mediated metabolism. The addition of the cytochrome P-450 inhibitor, cimetidine, significantly reduced the amount of acetaldehyde accumulating from ethanol when hepatocytes were incubated with either antipyrine or aminopyrine. Neither drug added directly to mitochondrial extracts inhibited the activity of aldehyde dehydrogenase. However, when neutralized extracts of hepatocytes that had undergone a 40-min incubation with ethanol and each drug were added to mitochondrial extracts, aldehyde dehydrogenase activity was substantially decreased. A greater inhibition was observed with neutralized extracts of hepatocytes from phenobarbital-treated rats. The results suggest that cytochrome P-450-generated metabolites of antipyrine and aminopyrine cause an inhibition of the low K(m) mitochondrial aldehyde dehydrogenase and thus an accumulation of acetaldehyde from ethanol.
Efthivoulou
M A
MA
Department of Medical Biochemistry, School of Medicine, Faculty of Health Sciences, Flinders University of South Australia, Adelaide, Australia.
Berry
M N
MN
D000079:Acetaldehyde / Q000378:metabolism*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000632:Aminopyrine / Q000494:pharmacology*; D000818:Animals; D000983:Antipyrine / Q000494:pharmacology*; D002478:Cells, Cultured; D002927:Cimetidine / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
D065607:Cytochrome P-450 Enzyme Inhibitors; D000632:Aminopyrine; D000431:Ethanol; D002927:Cimetidine; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; D000983:Antipyrine