Effect of P-450 inducers on glutathione (GSH) depletion by bromobenzene in primary cultures of dog hepatocytes.
Primary cultures of dog hepatocytes sensitivity responded to various inducers of cytochrome P-450; phenobarbital (PB) significantly elevated the activity of 7-ethoxycoumarin O-deethylase (ECOD) and progesterone 6 beta-hydroxylase (6 beta-OHP). beta-Naphthoflavone (beta-NF) and rifampicin (Rif) elevated the levels of 7-ethoxyresorufin O-deethylase (EROD) and 6 beta-OHP, respectively. When primary cultures of dog hepatocytes were incubated with bromobenzene, cellular reduced glutathione (GSH) levels decreased time- and dose-dependently. Pretreatment of the cultures with PB enhanced GSH depletion by bromobenzene, while beta-NF and Rif had little effect, suggesting that the 2B type cytochrome P-450 is responsible for the primary oxidation of bromobenzene to GSH-reactive metabolite(s). Bromobenzene-dependent GSH depletion was completely prevented by 10 microM SKF-525A both in the control and PB-treated primary cultures. Treatment of dog primary cultures with PB analogues also elevated the level of drug-metabolizing activity leading the cells to be more susceptible to GSH depletion by bromobenzene.
Harauchi
T
T
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Hirata
M
M
D000818:Animals; D001463:Barbiturates / Q000494:pharmacology; D001571:Benzoflavones / Q000494:pharmacology; D015153:Blotting, Western; D001969:Bromobenzenes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D004285:Dogs; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000096:biosynthesis / Q000378:metabolism; D011335:Proadifen / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D019324:beta-Naphthoflavone
D001463:Barbiturates; D001571:Benzoflavones; D001969:Bromobenzenes; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D005978:Glutathione; D012293:Rifampin