Metabolism of n-hexane by rat liver and extrahepatic tissues and the effect of cytochrome P-450 inducers.
1. The in vitro metabolism of n-hexane was studied in rat liver, lung, brain and skeletal muscle microsomes and in microsomes prepared from cell lines expressing human cytochrome P-450 2E1 or 2B6. The hydroxylated metabolites of n-hexane were quantified by gas chromatography-mass spectometry. 2. Rat liver and extensor digitorum longus (EDL, fast-twitch skeletal muscle) microsomes and the CYP 2B6 microsomes produced the pre-neurotoxic metabolite of n-hexane, 2-hexanol as a major metabolite in contrast to the other rat tissues examined. 3. Inhibition of 2- and 3-hexanol production from n-hexane by rat lung microsomes using metyrapone, an inhibitor of cytochrome P-450 2B1 activity, resulted in almost complete inhibition of lung microsomal activity. 4. Production of all three hexanols was significantly increased with phenobarbital-induced rat liver microsomes, with a 10-fold increase in 2- and 3-hexanol production. A slight increase in 2-hexanol production with phenobarbital-induced rat EDL and brain microsomes was observed. No increase in n-hexane metabolism was noted following induction with beta-naphthoflavone or with ethanol.
Crosbie
S J
SJ
Department of Environmental and Occupational Medicine, Medical School, University of Newcastle upon Tyne, Newcastle, UK.
Blain
P G
PG
Williams
F M
FM
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002460:Cell Line; D003314:Corn Oil / Q000494:pharmacology; D065702:Cytochrome P-450 CYP2B6; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D006586:Hexanes / Q000378:metabolism*; D000441:Hexanols / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010634:Phenobarbital / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D019324:beta-Naphthoflavone / Q000494:pharmacology
D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006586:Hexanes; D000441:Hexanols; C026385:n-hexane; D000431:Ethanol; D019324:beta-Naphthoflavone; D003314:Corn Oil; D003577:Cytochrome P-450 Enzyme System; C037076:2-hexanol; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital; D008797:Metyrapone