Effects of methyl ethyl ketone pretreatment on hepatic mixed-function oxidase activity and on in vivo metabolism of n-hexane

Abstract

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.