Metabolism of chloronitrobenzenes by isolated rat hepatocytes.
The metabolism of radiolabeled monochloronitrobenzene isomers was compared in isolated hepatocytes and hepatic subcellular fractions from male Fischer-344 rats. 2-Chloronitrobenezene was converted by isolated hepatocytes to 2-chloroaniline, 2-chloroaniline-N-glucuronide, and S-(2-nitrophenyl)glutathione in approximately equal quantities (13-19% of the added substrate in 90 min). The major metabolite formed from 3-chloronitrobenzene by isolated hepatocytes was 3-chloroaniline (31% of the added substrate in 90 min). Smaller amounts of 3-chloroaniline-N-glucuronide and 3-chloroacetanilide were formed (7 and 17% of the added 3-chloronitrobenzene, respectively, in 90 min). 4-Chloronitrobenzene was metabolized to 4-chloroacetanilide, 4-chloroaniline, and S-(4-nitrophenyl)glutathione in approximately equal amounts (10-15% of the added substrate in 90 min). Studies with hepatic microsomes showed that reduction of the chloronitrobenzenes to chloroanilines was inhibited by SKF 525-A, metyrapone, and carbon monoxide, suggesting that cytochrome P-450 played a role in the reaction. Thus, the major difference in the in vitro hepatic metabolism of the three isomers of chloronitrobenzene is the failure of 3-chloronitrobenzene to be converted to a glutathione conjugate.
Rickert
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Department of Drug Metabolism, Glaxo, Inc., Research Triangle Park, NC 27709.
Held
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D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009578:Nitrobenzenes / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013347:Subcellular Fractions / Q000378:metabolism
D004791:Enzyme Inhibitors; D009578:Nitrobenzenes