Characterization of the metabolites of methyl n-butyl ketone, methyl iso-butyl ketone, and methyl ethyl ketone in guinea pig serum and their clearance

Abstract

Methyl n-butyl ketone (MnBK) has been reported to produce peripheral neuropathy in experimental animals and in man. The metabolism of MnBK and related ketones was studies as part of a program to elucidate the molecular events in MnBK-induced neuropathy. Guinea pigs were given single 450 mg/kg ip doses of MnBK, methyl iso-butyl ketone (MiBK) or methyl ethyl ketone (MEK). Metabolites in serum were identified and quantitated by gas chromatography and gas chromatography-mass spectrometry. MnBK metabolites were 5-hydroxy-2-hexanone, 2,5-hexanedione, and 2-hexanol. MiBK was converted to 4-hydroxy-2-methyl-2-pentanone and 4-methyl-2-pentanol. MEK produced 2-butanol, 3-hydroxy-2-butanone, and 2,3-butanediol. The fate of several of the above metabolites was also investigated. Our results show that aliphatic ketones are metabolized both by reduction of the carbonyl group to form a secondary alcohol and by oxidation at the ω-1 carbon atom to form an hydroxylated ketone. Guinea pigs and other mammalian species receiving MnBK by various routes of administration showed qualitatively similar metabolic patterns in serum. Serum half-lives and clearance times for MnBK, MiBK, and MEK in the guinea pig were 78 min, 6 hr; 66 min, 6 hr; and 270 min, 12 hr; respectively. Our studies have shown that 2-hexanol, 5-hydroxy-2-hexanone, and 2,5-hexanediol may be neurotoxic by virtue of their conversion to the neurotoxin 2,5-hexanedione. n-Hexane, a reputed neurotoxin, was also investigated and was found to produce 5-hydroxy-2-hexanone and 2,5-hexanedione in guinea pig serum. The neurological effects of MnBK, n-hexane, and 2,5-hexanedione, therefore, may have a common metabolic origin.