Enalapril cytotoxicity in primary cultures of rat hepatocytes. I. Effects of cytochrome P450 inducers and inhibitors.
Enalapril maleate (EN) incubated with primary cultures of rat hepatocytes was cytotoxic in concentrations of 0.5 mM or greater. Toxicity was measured by release of lactate dehydrogenase (LDH) into the culture medium at 24 h. SKF525A, alpha-naphthoflavone (alpha NF) and metyrapone (MTP) reduced the toxicity of EN. In vivo pretreatment with phenobarbital (PB) and beta-naphthoflavone (beta NF) had minor protective effects on the responses of hepatocytes to EN exposure. However, in vivo pretreatment with pregnenolone-16 alpha-carbonitrile (PCN) substantially potentiated EN cytotoxicity. These results suggest that the cytocidal hepatotoxicity of EN in primary culture depends to some degree on metabolic activation by a cytochrome P450 species.
Jurima-Romet
M
M
Biochemical Toxicology Section, Drug Toxicology Division, Health and Welfare, Canada, Ottawa.
Huang
H S
HS
Paul
C J
CJ
Thomas
B H
BH
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004656:Enalapril / Q000037:antagonists & inhibitors / Q000633:toxicity*; D015773:Enalaprilat / Q000494:pharmacology*; D004789:Enzyme Activation; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008298:Maleates / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
D065607:Cytochrome P-450 Enzyme Inhibitors; D008298:Maleates; D004656:Enalapril; D003577:Cytochrome P-450 Enzyme System; C030272:maleic acid; D007770:L-Lactate Dehydrogenase; D015773:Enalaprilat