Inhalation of isopropanol: Induction of activating and deactivating enzymes in rat kidney and liver. Increased microsomal metabolism of n-hexane

Abstract

Rats were exposed to isopropanol by inhalation of 200, 2000 and 8000 ppm for 2 weeks with a daily exposure of 6 h. A pilot group exposed to 8000 ppm was given a recovery period of 4 weeks. Kidney and liver microsomal metabolism of n-hexane was investigated in vitro concomitant with activities of cytochrome P-450 and GSH enzymes and blood concentration of isopropanol and its metabolite acetone. A dose dependent increase was observed in the formation of all metabolites of n-hexane in both organs. Of special interest was the 9%, 80% and 198% increase of the preneurotoxic metabolite 2-hexanol in kidney microsomes. Cytochrome P-450 was increased 14%, 40% and 43% in kidney after 200, 2000 and 8000 ppm, respectively, and 10% and 19% in liver at 2000 and 8000 ppm. The activity of glutathione S-transferase was unaffected in kidney but elevated in liver, while GSH levels were elevated in both organs. The elevated level of kidney cytochrome P-450 did not return to normal during the 4-week-recobery period in contrast to liver cytochrome P-450. It is thus indicated that cytochrome P-450 and associated microsomal enzymes are more easily inducible and the changes more persistent in kidney than in liver. Our observations suggest that cytochrome P-450-mediated metabolic activation of n-hexane in the kidneys may have toxicological relevance in addition to liver metabolism, and that co-exposure to isopropanol and n-hexane mat represent an enhancement of the health hazard from n-hexane, possibly due to the isopropanol metabolite acetone.