Abstract
Metabolism of the environmental contaminant 2,6-dimethylnaphthalene (2,6-DMN) by rat liver microsomes and an NADPH-regenerating system led to the formation of three ring oxidation metabolites--2,6-dimethyl-3-naphthol, 2,6-dimethyl-3,4-naphthoquinone, and 3,4-dihydro-3,4-dihydroxy-2,6-dimethylnaphthalene--and one side chain oxidation metabolite--2-hydroxymethyl-6-methylnaphthalene. In addition, one metabolite remained unidentified. Pretreatment of rats with phenobarbital, 3-methylcholanthrene, Prudhoe Bay crude oil, or 2,6-DMN enhanced the rate of microsomal metabolism of 2,6-DMN 2-6-fold and significantly altered the metabolite profile. Liver microsomes from variously pretreated rats also enhanced the irreversible binding of 2,6-DMN[8-14C]N to microsomal protein. This binding to protein was inhibited by glutathione in a concentration-dependent manner. In vivo administration of 2,6-DMN to untreated rats led to a time-dependent depletion of hepatic glutathione levels. Both the rate and the extent of glutathione depletion were significantly enhanced in 3-methylcholanthrene-pretreated rats but not in phenobarbital-pretreated rats.
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Metabolism of 2,6-dimethylnaphthalene by rat liver microsomes and effect of its administration on glutathione depletion in vivo.
