G. Asins et al., THE EFFECT OF ETOMOXIR ON THE MESSENGER-RNA LEVELS OF ENZYMES INVOLVED IN KETOGENESIS AND CHOLESTEROGENESIS IN RAT-LIVER, Biochemical pharmacology, 47(8), 1994, pp. 1373-1379
The effects of acute treatment with 2-[6-(4-chlorophenoxy)hexyl]-oxira
ne-2- (etomoxir), an antiketonaemic and antidiabetic drug, on the mRNA
levels of several regulatory enzymes of ketogenesis, cholesterogenesi
s, and fatty acid synthesis in rats were determined. In rats treated w
ith etomoxir, mRNA levels for mitochondrial 3-hydroxy-3-methylglutaryl
-CoA (HMG-CoA) synthase and carnitine palmitoyl transferase I (CPT I)
remained unchanged, while mRNA levels for carnitine palmitoyl transfer
ase II (CPT II) significantly increased 2-fold. Injection of etomoxir
produced no effect on the mRNA levels of cytosolic HMG-CoA synthase bu
t increased the mRNA levels of HMG-CoA reductase 2.5-fold. Etomoxir le
d to a 3-fold increase in the mRNA levels of fatty acid synthase of ra
ts under acute treatment. Rats fed with a fat diet significantly incre
ased the expression of mitochondrial HMG-CoA synthase, CPT I and CPT I
I 3-fold in all cases, while 2-(diethylhexyl)phthalate (DEHP) produced
increases in the expression of these genes (5-, 4- and 12-fold, respe
ctively). The mRNA levels of HMG-CoA reductase were not changed by eit
her DEHP or fat diet, while DEHP increased cytosolic HMG-CoA synthase
2.5-fold. DEHP did not change the mRNA levels for fatty acid synthase.
It was concluded that etomoxir does not produce its hypoketonaemic, h
ypocholesteraemic or hypolipogenic effects through changes in the gene
tic expression of the regulatory enzymes of these pathways, but probab
ly due to the shortage of their common substrate, acetyl-CoA, because
of the inhibitory action on CPT I.