Bromobenzene-glutathione excretion into bile reflects toxic activation of bromobenzene in rats.
This investigation was designed to determine whether biliary excretion of bromobenzene(BB)-glutathione(GSH) conjugate can be used as an index of in vivo activation of BB. In order to test this hypothesis, the effect of chemicals known to alter the toxicity and biotransformation of BB (i.e., cytochrome P-450 inducers and inhibitors) on the biliary excretion of BB-GSH was studied in rats. BB-GSH was the major BB metabolite in bile. A linear relationship was observed between the dosage of BB administered and BB-GSH excreted into bile, up to a dosage of 250 mumol/kg of BB. Of the inducers tested, phenobarbital, which is known to increase the toxicity of BB, dramatically increased (700%) the rate of biliary excretion of BB-GSH over that in control animals. In contrast, 3-methylcholanthrene, which is known to decrease the hepatotoxicity of BB, decreased the biliary excretion of BB-GSH (56%). Inhibitors of P-450, such as SKF 525-A and piperonyl butoxide which are known to decrease the activation and hepatotoxicity of BB, also decreased the biliary excretion of BB-GSH. These findings are in agreement with the hypothesis that the biliary excretion of BB-GSH reflects the formation of the reactive BB metabolite in liver and the rate of biliary excretion can be used to determine factors that are important in determining the toxicity of BB.
Madhu
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Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66103.
Klaassen
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D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D001711:Biotransformation; D001969:Bromobenzenes / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011136:Polysorbates / Q000494:pharmacology; D051381:Rats
D001969:Bromobenzenes; D011136:Polysorbates; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; C032036:bromobenzene; D005978:Glutathione; D010634:Phenobarbital