Metabolism of 2,6-dimethylnaphthalene by rat liver microsomes and effect of its administration on glutathione depletion in vivo.
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.
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D009281:Naphthalenes / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
D009281:Naphthalenes; C028519:2,6-dimethylnaphthalene; D005978:Glutathione