Amplification of palmitate-induced inhibition of cholesterol biosynthesis in cultured rat hepatocytes by garlic-derived organosulfur compounds

Incubation of primary cultured rat hepatocytes in the presence of sodium palmitate led to a concentration-dependent inhibition of [C-14]acetate incorporation into non-saponifiable lipids, particularly cholesterol. This inhibition was enhanced by water-soluble extracts of garlic powder (Kwai(R), Sapec(R)). Comparative studies using different garlic derived organosulfur compounds and related chemicals revealed that the amplification was mainly due to diallyl disulfide (DADS) which was effective at concentrations as low as 5 mu M. With the exception of allyl mercaptan which was 10-fold less potent the other compounds tested were ineffective indicating specific structural requirements of this interaction with the palmitate-induced inhibition. Replacement of labeled acetate by labeled mevalonate omitted both inhibition by palmitate and amplification by DADS. Furthermore, palmitate did not influence the DADS-induced changes in the pattern of sterols produced. These results suggest that garlic-derived allylsulfides, especially DADS, interact with the phosphorylation cascade of HMGCoA-reductase which is stimulated by incubation with palmitate presumably via increasing the intracellular level of palmitoyl-CoA. In conclusion, interference with endogeneous regulatory mechanisms may provide an efficent, highly sensitive and physiologically compatible way by which garlic components might influence cholesterol biosynthesis.