Stereospecificity of the inhibition by etomoxir of fatty acid and cholesterol synthesis in isolated rat hepatocytes.
The racemates of substituted 2-oxiranecarboxylates are potent inhibitors of fatty acid oxidation and fatty acid and cholesterol synthesis. We show in the accompanying paper [Agius L, Peak M and Sherratt HSA, Biochem Pharmacol 42: 1711-1715, 1991] that only the R-enantiomer of etomoxir, a potent hypoglycaemic compound, inhibits fatty acid oxidation in hepatocytes. We demonstrate in this paper that although the R-enantiomer of etomoxir is esterified to its CoA-ester more readily than the S-enantiomer, both the R- and S-enantiomers are equally potent inhibitors of fatty acid and cholesterol synthesis from acetate in rat hepatocytes. The inhibition of fatty acid synthesis is not due to direct inhibition of fatty acid synthetase and the inhibition of cholesterol synthesis occurs at a site proximal to formation of mevalonate. Since the S-enantiomer inhibits fatty acid and cholesterol synthesis but not fatty acid oxidation the inhibition of the biosynthetic pathways is not coupled to inhibition of fatty acid oxidation.
Department of Medicine, University of Newcastle upon Tyne, U.K.
L
L
Agius
E J
EJ
Meredith
H S
HS
Sherratt
D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D003065:Coenzyme A / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors; D005227:Fatty Acids / Q000096:biosynthesis*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D004852:Epoxy Compounds; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D002784:Cholesterol; D064429:Fatty Acid Synthases; C054207:etomoxir; D003065:Coenzyme A