Rat lung and liver microsomal cytochrome P-450 isozymes involved in the hydroxylation of n-hexane.

The primary metabolism of n-hexane in rat lung and liver microsomes was investigated. In liver microsomes from untreated animals the formation of each of the metabolites, 1-, 2- and 3-hexanol, was best described kinetically by a two-enzyme system, whereas for lung microsomes a one-enzyme system was indicated for each metabolite. Cytochrome P-450-PB-B, the major cytochrome P-450 isozyme induced in rat liver by phenobarbital, appeared to be responsible for the formation of 2- and 3-hexanol in lung microsomes from untreated rats as judged by antibody inhibition studies. The presence of this isozyme was confirmed by immunoblotting. In contrast, formation of 1-hexanol in rat lung was catalyzed by a cytochrome P-450 isozyme different from the major isozymes induced by either phenobarbital or beta-naphthoflavone. Similarly, formation of 2,5-hexanediol from 2-hexanol was catalyzed by a P-450 isozyme different from cytochrome P-450-PB-B and present in liver but not in lung microsomes. Furthermore, alcohol dehydrogenase activity with hexanols or hexanediol as the substrate was found exclusively in liver cytosol. These results suggest that inhaled n-hexane must be transported to the liver either intact or in the form of 2-hexanol before the neurotoxic metabolite 2,5-hexanedione can be formed.