Induction of cytochrome P450 isozymes by simultaneous inhalation exposure of hens to n-hexane and methyl iso-butyl ketone (MiBK).
Lapadula-DM; Habig-C; Gupta-RP; Abou-Donia-MB
Biochem Pharmacol 1991 Mar; 41(6/7):877-883
Induction of cytochrome-P-450 (P450) isozymes by n-hexane (110543) (hexane) and methyl-isobutyl-ketone (108101) (MIBK) was studied in hens. Young hens were exposed to 0 or 1000 parts per million (ppm) hexane, 1000ppm MIBK, or 1000ppm hexane plus 10, 100, 250, 500, or 1000ppm MIBK vapor for 29 days and observed for clinical signs of toxicity. The hens were killed at 29 days and the livers were removed and assayed for P450, benzphetamine-N-demethylase (BzND), ethoxyresorufin-O-deethylase (EROD), and cytochrome-c-reductase (cyt- c-red). P450 isozymes were analyzed using rabbit antibodies raised against isozymes from phenobarbital and beta-naphthoflavone (BNF) treated hens. Hepatic microsomes from hens that had been exposed to 1000ppm MIBK or hexane were incubated with carbon-14 labeled hexane. The extent of metabolism to 2-hexanone (591786), gamma- valerolocatone (108292) (gVL), and 2,5-hexanedione (110134) (25HD) was determined. Hens exposed to hexane plus MIBK lost weight in a dose dependent manner. The greatest decreases occurred in animals exposed to 1000ppm hexane plus 250, 500, and 1000ppm MIBK. These exposures also caused mild to severe ataxia. Hens exposed to 1000ppm MIBK and 1000ppm hexane plus 100, 250, 500, and 1000ppm MIBK had significantly increased hepatic P450 concentrations. All exposures significantly increased hepatic BzND activity. EROD and cyt-c-red activities were not affected in a consistent, dose related manner. The in-vitro metabolism of hexane to 25HD and gVL was significantly increased in microsomes from MIBK exposed hens. Hexane, MIBK, and the combined exposures caused significant dose related increases in three P450 isozymes, two of which were phenobarbital inducible and one that was BNF inducible. The largest increase was a 200 to 750% increase in a phenobarbital inducible isozyme induced by MIBK which accounted for more than 70% of the total P450 content.
NIOSH-Publication; NIOSH-Grant; In-vivo-studies; Laboratory-animals; Aliphatic-hydrocarbons; Ketones; Organic-solvents; Inhalation-studies; Neurotoxic-effects; Synergism; Liver-enzymes; Enzyme-complexes; In-vitro-studies; Biotransformation
Pharmacology Duke University Department of Pharmacology Durham, N C 27710
110-54-3; 108-10-1; 591-78-6; 108-29-2; 110-13-4
Neurotoxic Disorders; Neurotoxic-effects
Duke University, Durham, North Carolina