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Oxidative biotransformation of oxazepam to reactive and nonreactive products in rat, mouse and human microsomes

Chemistry Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709

LT Burka

Chemistry Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709

KB Demby

Office of Academic and Student Programs, UNC School of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA

1 The oxidative metabolism of oxazepam by human, B6C3F1 mouse and F344 rat microsomes was examined. The major metabolite in all three species was 6-chloro-4- phenyl-2(1H)-quinazolinecarboxylic acid (CPQ-carboxylic acid). In addition, rat microsomes produced 4'-hydroxyox azepam and oxazepam-dihydrodiol in NADPH-containing incubations.

2 Covalent protein adducts were increased by the addi tion of NADPH to rat and mouse microsomes but not human microsomes. The magnitude of adduct formation was rats > mice > humans.

3 Formation of oxazepam-dihydrodiol was reduced by the addition of cyclohexene oxide and GSH to the incuba tions. Two additional metabolites were produced under these conditions. One of these was tentatively identified as a GSH conjugate. Covalent adduct formation was unaffect ed by GSH or cyclohexene oxide.

4 These results suggest that adduct formation occurred via an unknown reactive product rather than via oxazepam-epoxide, and that the relative rates of oxidative metabolism in vitro parallel that in vivo for the three species examined.

Key Words: oxazepam • microsomes • biotransformation • adducts • dihydrodiol

Human & Experimental Toxicology, Vol. 14, No. 10, 779-786 (1995)
DOI: 10.1177/096032719501401001


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