INFLUENCE OF ETOMOXIR ON THE EXPRESSION OF SEVERAL GENES IN LIVER, TESTIS AND HEART

1. The effect of ethyl-2-[6-(4-chlorophenoxy)hexyl] oxirane-2-carboxyl ate (etomoxir) and its oxirane analogues on the expression of several genes from liver and testis as well as the beneficial effect of etomox ir on heart performance and myosin isozyme expression is reviewed. 2. In liver, the effect of etomoxir, alone or in combination With fat or di-(2-eihylhexyl)phthalate (DEHP) on the expression of several genes r elated to lipid metabolism has been studied. The simultaneous addition of etomoxir and a fat diet produces an increase in the expression of carnitine palmitoyl transferase (CPT) I, cytochrome P-450 4A1 omega-hy droxylase and fatty acid binding protein (L-FABP). The mRNA levels of other genes such as CPT II, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) r eductase, and fatty acid synthase (FAS) are increased by etomoxir alon e. Neither cytosolic nor mitochondrial HMG-CoA synthase have any signi ficant effect on the mRNA levels induced by etomoxir. A probably frequ ent mechanism for the action of etomoxir may involve the overload of n on-metabolized fatty acids produced after the inhibition of CPT I by t he oxirane compounds. There is some speculation as to whether the pero xisome proliferator activated receptor (PPAR) increases its participat ion in the expression, under the action of etomoxir. 3. In testis, the changes in several genes related to cholesterogenesis, ketogenesis, f atty acid synthesis and transport of fatty acids into mitochondria hav e also been reviewed. Etomoxir in testis does not appear to produce an y effect either alone or in combination with DEHP or a fat diet. 4. In heart, the action of etomoxir has not been studied at the transcripti onal level.,Etomoxir enhances the function of either ischemic or diabe tic rats, increasing glucose oxidation and heart performance and produ cing an atypical left hypertrophy. The biochemical action is probably due to an increase in pyruvate dehydrogenase activity together with a change in myosin isozyme expression.