Functional Cyp2e1 is required for substantial in vivo formation of 2,5-hexanedione from n-hexane in the mouse

Neurotoxicity of n-hexane is mediated by its metabolite 2,5-hexanedione (2, 5-HD). Cytochrome P4502E1 (CYP2E1) has been suggested but not shown to be i nvolved in the formation of the metabolite. An objective of the current stu dy was to assess the essentiality of CYP2E1 for in vivo 2,5-HD formation fr om n-hexane. This was accomplished by comparing urinary levels of the gamma -diketone in n-hexane-treated mice in which the Cyp2e1 gene has been delet ed(Cyp2e1(-/-)) with that in n-hexane-treated wild-type (Cyp2e1(+/+)) mice. 2,5-HD was detectable not as the free compound but as further metabolites, at levels that were comparable in both strains of mice, following a daily 200 mg/kg i.p. dose of the alkane for 10 days. Continued daily n-hexane tre atment resulted in increased urinary levels of 2,5-HD metabolites in Cyp2e1 (+/+) but not in Cyp2e1(-/-) mice. Only in Cyp2e1(+/+) mice and only on day 21 of n-hexane treatment was a trace level of unchanged 2,5-HD detected. 3 -Hexanol was the only other n-hexane metabolite detected in the mice but it s concentration was higher in Cyp2e1(-/-) than in Cyp2e1(+/+) mice. In n-he xane-treated rats, in contrast to mice, multiple metabolites of the alkane, including unchanged 2,5-HD, were detected. The results indicate that subst antial in vivo formation of 2,5-HD from n-hexane in the mouse requires CYP2 E1, and suggest that further detoxification of the metabolite may be very e fficient in this species.