Induction of cytochrome P450 isozymes by simultaneous inhalation exposure of hens to n-hexane and methyl iso-butyl ketone (MiBK).
Chickens were exposed simultaneously to the industrial hexacarbon solvents n-hexane and methyl iso-butyl ketone (MiBK). n-Hexane has been shown to be neurotoxic in both humans and other vertebrates. While MiBK is not neurotoxic, it has been shown to greatly synergize the clinical appearance of neurotoxicity in animals exposed to both of these solvents. Groups of hens were exposed for 29 days in inhalation chambers to 1000 ppm n-hexane in combination with 10, 100, 250, 500, or 1000 ppm MiBK. Other groups received either 1000 ppm n-hexane, 1000 ppm MiBK, or ambient air and served as controls. A dose-dependent decrease in body weight and an increase in clinical effects were noted for the highest exposure groups (1000 ppm n-hexane combined with 1000, 500 or 250 ppm MiBK). There was an MiBK dose-dependent increase in cytochrome P450 content and benzphetamine N-demethylase activity, but there was no distinct pattern for ethoxyresorufin O-deethylase or cytochrome c reductase activities. Mixed-function oxidase levels and activities (cytochrome P450 content and benzphetamine N-demethylase) were elevated significantly (P less than 0.05) over controls even in the lowest MiBK group (10 ppm), although there were no clinical signs of neurotoxicity. Four different isozymes of cytochrome P450 were measured immunologically. There was a dose-dependent increase in three of the isozymes, two of which were phenobarbital inducible and one of which was induced by beta-napthoflavone. Quantitatively, the largest increase was in the PB-A isozyme, a phenobarbital-inducible isozyme which accounted for approximately 70% of the cytochrome P450 present in animals treated with MiBK. The results suggest that MiBK selectively induces cytochrome P450 isozymes leading to the metabolic activation of the weak neurotoxicant n-hexane to the potent neurotoxicant 2,5-hexanedione (2,5-HD).
Lapadula
D M
DM
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
Habig
C
C
Gupta
R P
RP
Abou-Donia
M B
MB
D000280:Administration, Inhalation; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002645:Chickens; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation; D006586:Hexanes / Q000008:administration & dosage / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D008742:Methyl n-Butyl Ketone / Q000008:administration & dosage / Q000494:pharmacology*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism
D006586:Hexanes; D007527:Isoenzymes; C026385:n-hexane; D008742:Methyl n-Butyl Ketone; D003577:Cytochrome P-450 Enzyme System; C019781:benzphetamine N-demethylase; D010089:Oxidoreductases, N-Demethylating; C005458:methyl isobutyl ketone