Inhalation of isopropanol: induction of activating and deactivating enzymes in rat kidney and liver. Increased microsomal metabolism of n-hexane.
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-recovery 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 coexposure to isopropanol and n-hexane may represent an enhancement of the health hazard from n-hexane, possibly due to the isopropanol metabolite acetone.
D000433:1-Propanol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000096:Acetone / Q000097:blood; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects*; D005740:Gases; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006586:Hexanes / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains
D005740:Gases; D006586:Hexanes; D000096:Acetone; C026385:n-hexane; D003577:Cytochrome P-450 Enzyme System; D000433:1-Propanol; D005982:Glutathione Transferase; D005978:Glutathione