The accumulation and metabolism of 3-trifluoromethylpyridine by rat olfactory and hepatic tissues.
The accumulation of [methyl-14C]3-trifluoromethylpyridine (14C-3-FMP) by rat olfactory and hepatic tissue in vivo and in vitro has been investigated. 14C-3-FMP accumulates rapidly and selectively in both tissues in vivo, with an appreciable proportion of this activity being associated with the protein macromolecular fractions. Similar results were seen when isolated tissues were incubated in vitro in the presence of 14C-3-FMP. Studies with a range of metabolic inhibitors demonstrated that accumulation into olfactory tissue in vitro was virtually abolished by metyrapone and SKF-525A, indicating a key role of cytochrome P-450 mediated metabolism in this process. This was substantiated further by the in vivo inhibition of accumulation by metyrapone. Studies on the in vitro metabolism of 14C-3-FMP by isolated rat olfactory tissue demonstrated the major metabolite to be 3-trifluoromethylpyridine-N-oxide (3-FMP N-oxide) which is known to cause olfactory and hepatic toxicity in the rat. Metyrapone, while inhibiting accumulation of radioactivity derived from both 14C-3-FMP and 14C-3-FMP N-oxide in this tissue in vitro, only inhibited the synthesis of this metabolite by approximately 60%, indicating that several metabolic stages are involved in the metabolism and accumulation of 14C-3-FMP.
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ICI Central Toxicology Laboratory, Macclesfield, Cheshire, U.K.
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D000818:Animals; D001345:Autoradiography; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D009831:Olfactory Mucosa / Q000187:drug effects / Q000378:metabolism*; D011335:Proadifen / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism* / Q000633:toxicity; D051381:Rats
D011725:Pyridines; C056508:3-trifluoromethylpyridine; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D008797:Metyrapone