The role of metabolism and covalent binding in the cytotoxicity of a nitrogen-containing steroid toward rat hepatocytes.
The nitrogen-containing steroid N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (I) causes concentration- and time-dependent cytotoxicity toward freshly isolated F-344 rat hepatocytes. Because hepatocytes extensively metabolize I to both stable and reactive products, the role of metabolism and covalent binding in the cytotoxicity of I was investigated. Concentration-dependent covalent binding of I-related material to hepatocyte macromolecules was detected. Treatment of rats with phenobarbital increased the rate and extent of hepatocyte metabolism of I, increased the covalent binding of I-related material to hepatocyte macromolecules, but decreased the cytotoxicity of I. Addition of testosterone to incubations of hepatocytes and I inhibited the metabolism of I, decreased the covalent binding of I-related material to hepatocyte macromolecules, but potentiated the cytotoxicity of I. These results indicate that the covalent binding of reactive metabolites is not involved in the cytotoxicity of I. Moreover, the two major metabolites of I, the 4-carbinolamide and monoethyl analog, were much less cytotoxic toward hepatocytes than I. These data suggest that the metabolism of I represents detoxication and that the parent compound is the cytotoxicant.
Kedderis
G L
GL
Department of Animal Drug Metabolism, Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065.
Argenbright
L S
LS
Miwa
G T
GT
D000818:Animals; D001378:Azasteroids / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D001711:Biotransformation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D046911:Macromolecular Substances; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013260:Steroids, Heterocyclic / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology*
D001378:Azasteroids; D046911:Macromolecular Substances; D013260:Steroids, Heterocyclic; D013196:Dihydrotestosterone; D013739:Testosterone; C031563:17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one