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-carboxylate (etomoxir) and its oxirane analogues on the expression of several genes from liver and testis as well as the beneficial effect of etomoxir 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-ethylhexyl)phthalate (DEHP) on the expression of several genes related 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-hydroxylase and fatty acid binding protein (L-FABP). The mRNA levels of other genes such as CPT II, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, and fatty acid synthase (FAS) are increased by etomoxir alone. Neither cytosolic nor mitochondrial HMG-CoA synthase have any significant effect on the mRNA levels induced by etomoxir. A probably frequent mechanism for the action of etomoxir may involve the overload of non-metabolized fatty acids produced after the inhibition of CPT I by the oxirane compounds. There is some speculation as to whether the peroxisome proliferator activated receptor (PPAR) increases its participation in the expression, under the action of etomoxir. 3. In testis, the changes in several genes related to cholesterogenesis, ketogenesis, fatty acid synthesis and transport of fatty acids into mitochondria have also been reviewed. Etomoxir in testis does not appear to produce any effect either alone or in combination with DEHP or a fat diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Hegardt
F G
FG
Unit of Biochemistry, University of Barcelona School of Pharmacy, Spain.
Serra
D
D
Asins
G
G
D000818:Animals; D004852:Epoxy Compounds / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006321:Heart / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D013737:Testis / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*
D004852:Epoxy Compounds; D007004:Hypoglycemic Agents; C054207:etomoxir