The detection of cytotoxicity produced by short-lived reactive intermediates: a study with bromobenzene.
1. A V79 cell incubation incorporating rat liver 9000 g supernatant (S9) fractions, used previously to detect the toxicity due to long-lived, stable metabolites of cyclophosphamide, has been used to study the toxicity of short-lived, reactive metabolites generated from bromobenzene. 2. Cytotoxicity was observed in the presence of S9 fractions from rats treated with phenobarbitone but not in the presence of S9 fractions from untreated or beta-naphthoflavone-treated animals. This toxicity was enhanced by depletion of the glutathione in the S9 fraction by prior treatment of the animals with diethyl maleate and was reduced by SKF 525 A, in agreement with results in vivo on the mechanism of bromobenzene-induced hepatotoxicity. 3. This study demonstrates that cytotoxicity due to the generation of short-lived, reactive metabolites can be detected in this system in vitro provided that procedures are used to modify the activating and detoxifying enzyme systems within the S9 fraction.
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D001969:Bromobenzenes / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D003374:Coumarins / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D010090:Oxidoreductases, O-Demethylating / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000378:metabolism
D001969:Bromobenzenes; D002273:Carcinogens; D003374:Coumarins; C017299:7-ethoxycoumarin; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; C047335:7-methoxycoumarin-O-demethylase; D010090:Oxidoreductases, O-Demethylating; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D005978:Glutathione