An investigation into the role of rat skeletal muscle as a site for xenobiotic metabolism using microsomes and isolated cells.
1. The role of skeletal muscle microsomes as a site of extrahepatic xenobiotic metabolism using n-hexane as a model substrate was investigated. The observed cytochrome P450-dependent metabolism was compared with that found with liver, and brain microsomal fractions. 2. Rat skeletal muscle microsomes metabolised n-hexane to 1-, 2- and 3-hexanol at rates 40-300 times lower than observed with rat liver microsomes. 3. Fast-twitch extensor digitorum longus muscle (EDL) microsomes had twice as much n-hexane hydroxylase activity as the slow-twitch soleus and furthermore the EDL microsomes produced 2-hexanol, a bioactivation product of n-hexane, as a major metabolite. 4. Metabolism of hexane to 1-, 2- and 3-hexanol and 2-hexanon was demonstrated in cultured rat myoblasts. 5. Ethoxyresorufin and pentoxyresorufin O-dealkylation were not detected in either muscle microsomes or myoblasts although immunocytochemical localisation studies were suggestive of the presence of cytochrome P-450. 6. In conclusion, rat skeletal muscle has a low level of xenobiotic metabolism activity. The relevance to neuromuscular toxicity of n-hexane is discussed.
Crosbie
S J
SJ
Department of Environmental and Occupational Medicine, Medical School, University of Newcastle upon Tyne, UK.
Blain
P G
PG
Williams
F M
FM
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D008401:Gas Chromatography-Mass Spectrometry; D006586:Hexanes / Q000378:metabolism* / Q000633:toxicity; D000441:Hexanols / Q000378:metabolism; D007150:Immunohistochemistry; D007527:Isoenzymes; D008297:Male; D008742:Methyl n-Butyl Ketone / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D006586:Hexanes; D000441:Hexanols; D007527:Isoenzymes; C026385:n-hexane; C036260:1-hexanol; D008742:Methyl n-Butyl Ketone; D003577:Cytochrome P-450 Enzyme System; C037076:2-hexanol; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D009251:NADPH-Ferrihemoprotein Reductase