An investigation into the role of rat skeletal muscle as a site for xenobiotic metabolism using microsomes and isolated cells

Abstract

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 com pared with that found with liver, and brain micro somal 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- hexanone 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.