Effects of methyl ethyl ketone pretreatment on hepatic mixed-function oxidase activity and on in vivo metabolism of n-hexane.
1. Male Fischer-344 rats were given methyl ethyl ketone (MEK; 1.87 ml/kg), a potentiator of the neurotoxicity of n-hexane, by gavage for 4 days prior to a single inhalation exposure to n-hexane (1000 ppm). 2. Samples of blood, liver, testis and sciatic nerve were obtained and analysed for n-hexane, MEK and their metabolites by g.l.c.-mass spectrometry. 3. Pretreatment with MEK increased the concentrations of 2,5-hexanedione (2,5-HD; the proximal neurotoxin) in blood, sciatic nerve and testis relative to concentrations in the tissues in sham-treated controls. 4. Concentrations of 2,5-dimethylfuran, a metabolite of 2,5-HD, were increased in all four tissues tested. 5. After 1-7 days treatment with MEK, the activity of 7-ethoxycoumarin O-deethylase was increased (up to 500%), but benzphetamine N-demethylase activity was virtually unaffected. 6. Hence, the potentiating effects of MEK on the neurotoxicity of n-hexane appear to arise, at least in part, from the activating effects of MEK on selected microsomal enzymes responsible for n-hexane activation.
Department of General and Biochemical Toxicology, Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
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Robertson
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White
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Bus
D000818:Animals; D002074:Butanones / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006586:Hexanes / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology* / Q000648:ultrastructure; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D002074:Butanones; D006586:Hexanes; C026385:n-hexane; C005222:methylethyl ketone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases