Metabolites and ketone body production following methyl n-butyl ketone exposure as possible indices of MnBK potentiation of carbon tetrachloride hepatotoxicity.
While the biotransformation of methyl n-butyl ketone (MnBK) in animals is well characterized, little is known about the quantitative relationship between hepatic and plasma MnBK concentrations. This study provides such information and emphasizes the usefulness of MnBK metabolite quantification, as well as MnBK-induced metabolic ketosis for the biological monitoring of MnBK exposure in rats. Elimination of MnBK was followed 24 hr after oral administration (0.95, 1.90, and 5.70 mmol/kg in corn oil) to male Sprague-Dawley rats. Two metabolites [2-hexanol (2HOL), and 2,5-hexanedione (2,5HD)] were also monitored and their kinetics determined. These data were compared to ketone body (KB) concentrations found in plasma and liver during the same period. Plasma concentrations of MnBK and 2,5HD correlated well with those in the liver. This was not the case for 2HOL. MnBK, 2HOL, and 2,5HD were no longer detected in plasma and liver 18 hr after dosing. Meanwhile, a marked ketosis was observed from 12 to 24 hr. This ketotic state was due to an increase in beta-hydroxybutyrate (BOHB), while acetoacetate remained at its basal levels. These data indicate that MnBK can induce ketosis in rats and suggest that the resulting BOHB might be used as an alternative biological monitor of MnBK exposures at high concentrations.
D000284:Administration, Oral; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002849:Chromatography, Gas; D004357:Drug Synergism; D007659:Ketones / Q000378:metabolism*; D007662:Ketosis / Q000139:chemically induced; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008742:Methyl n-Butyl Ketone / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D007659:Ketones; D008742:Methyl n-Butyl Ketone; D002251:Carbon Tetrachloride