In vitro inhibition of carnitine acyltransferase activity in mitochondria from rat and mouse liver by a diethylhexylphthalate metabolite.
The effects of mono(2-ethyl-5-oxohexyl)phthalate [ME(O)HP], a di(2-ethylhexyl)phthalate (DEHP) metabolite and a potent peroxisomal inducer, on the mitochondrial beta-oxidation were investigated. In isolated rat hepatocytes, ME(O)HP inhibited long chain fatty acid oxidation and had no effect on the ketogenesis of short chain fatty acids, suggesting that the inhibition occurred at the site of carnitine-dependent transport across the mitochondrial inner membrane. In rat liver mitochondria, ME(O)HP inhibited carnitine acyltransferase I (CAT I; EC 2.3.1.21) competitively with the substrates palmitoyl-CoA and octanoyl-CoA. An analogous treatment of mouse mitochondria produced a similar competitive inhibition of palmitoyl-CoA transport whereas ME(O)HP exposure with guinea pig and human liver mitochondria revealed little or no effect. The addition of clofibric acid, nafenopin or methylclofenopate revealed no direct effects upon CAT I activity. Inhibition of transferase activity by ME(O)HP was reversed in mitochondria which had been solubilized with octyl glucoside to expose the latent form of carnitine acyltransferase (CAT II), suggesting that the inhibition was specific for CAT I. Our results demonstrate that in vitro ME(O)HP inhibits fatty acid oxidation in rat liver at the site of transport across the mitochondrial inner membrane with a marked species difference and support the idea that induction of peroxisome proliferation could be due to an initial biochemical lesion of the fatty acid metabolism.
Grolier
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Imperial Chemical Industries p.l.c., Central Toxicology Laboratory, Macclesfield, Cheshire, U.K.
Elcombe
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D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002210:Caprylates / Q000378:metabolism; D002333:Carnitine Acyltransferases / Q000037:antagonists & inhibitors*; D004051:Diethylhexyl Phthalate / Q000378:metabolism / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism; D005960:Glucosides; D006168:Guinea Pigs; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008830:Microbodies / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D010168:Palmitates / Q000378:metabolism; D010795:Phthalic Acids / Q000494:pharmacology*; D051381:Rats
D002210:Caprylates; D005227:Fatty Acids; D005960:Glucosides; D010168:Palmitates; D010795:Phthalic Acids; C018619:octyl-beta-D-glucoside; C080276:mono(2-ethyl-5-oxohexyl)phthalate; D004051:Diethylhexyl Phthalate; D002333:Carnitine Acyltransferases; C031492:octanoic acid