Evidence that chlorpromazine inhibits sterologenesis at post-HMGCoA reductase sites in rat liver, in vitro.
The mechanism by which chlorpromazine inhibits cholesterogenesis in rat liver was investigated in vitro with the use of [14C] acetate and [14C] mevalonate as sterol precursors. Evidence was obtained that chlorpromazine blocks cholesterogenesis at multiple sites beyond HMGCoA reductase (beta-hydroxy-beta-methylglutarylCoA reductase, EC 1.1.1.34), the rate-limiting step. Squalene synthesis from both labeled acetate and mevalonate is reduced to a similar extent in the presence of chlorpromazine (29-36% at 0.5 mM). The data indicate that there is also an impairment of conversion of squalene to lanosterol, and of lanosterol to cholesterol. Overall inhibition of cholesterogenesis by chlorpromazine reached 65-75% at 0.5 mM and was concentration-dependent over the range 0.15-1.0 mM.
D000818:Animals; D002746:Chlorpromazine / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D051381:Rats; D013185:Squalene / Q000378:metabolism; D013261:Sterols / Q000096:biosynthesis*
D013261:Sterols; D013185:Squalene; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid; D002746:Chlorpromazine