Garlic preparations have been shown to exert hypocholesteremic effects in animals and man. Recent research in vitro has revealed multiple interactions of garlic compounds with the biosynthetic pathway for cholesterol in rat liver resulting in moderate but significant inhibition. Using rat hepatocytes in primary culture we can demonstrate that the incorporation of 14C-labelled acetate into non-saponifiable lipids was influenced mainly on two levels; (i) at the level of HMGCo-A reductase and (ii) at late steps of the biosynthetic pathway, particularly at lanosterol 14 demethylase. Overall inhibition caused by garlic extracts at 0.5 mg/ml ranged within 20 to 30% during a period of 2 h. With regard to the first influence it was noted that at low concentrations of garlic compounds no direct inhibition of HMGCoA reductase occurred, but the activity was inhibited via several indirect mechanisms involving different signal transduction pathways. The most important interaction seemed to be the amplification of the AMP-dependent kinase-mediated phosphorylation of HMGCoA reductase by garlic-derived organosulfur compounds, particularly diallyldisulfide (DADS). This influence was detectable down to 1 uM DADS and was apparent with changes of intracellular AMP as well as the palmitoyl-CoA induced stimulation of the respective kinase-kinase. Thus, this sensitive mechanism not only affects hepatic cholesterol biosynthesis but also fatty acid biosynthesis via acetyl-CoA carboxylase in a concerted action. It is conceivable that a similar type of interactions occurs in other tissues expressing a similar AMP-dependent kinase such as mammary gland and adipose tissue. Another mechanism of comparable sensitivity was the amplification of the adenosine-induced inhibition by allicin at the level of the adenosine receptor. This influence seemed to be mediated via adenosine-induced changes in intracellular Ca2+ rather than cAMP.

With respect to the later steps of cholesterol biosynthesis the inhibition of lanosterol -demethylase by allicin and ajoene was most important leading to complete inhibition at concentrations above 50 and 300 uM, respectively. At lower concentrations the partial inhibition of this enzyme probably causes the accumulation of intermediates of lanosterol synthesis which in turn may inhibit HMGCoA reductase.

Table 1 Advantages of garlic-derived organosulfur compounds as inhibitors of cholesterol biosynthesis.
1	They enhance in a sensitive manner the physiological mechanisms that reduce endogenous cholesterol biosynthesis resulting in a high bio-compatibility of their effects.
2	They exert multiple different actions leading to a balanced response of the cells and the whole organism.
3	They exert only partial inhibition preventing depletion of important terpenoid intermediates of cholesterol biosynthesis.
4	Presumably (due to their mode of action) they do not affect cholesterol biosynthesis in organs that need this molecule for production of hormones and other functions.
5	They do not seem to produce adverse effects during long-term application of garlic preparations.