Inhibition of sterol 4alpha-methyl oxidase is the principal mechanism by which garlic decreases cholesterol synthesis.

Clinical and experimental evidence indicates that garlic ingestion lowers blood cholesterol levels, and treatment of cells in culture with garlic and garlic-derived compounds inhibits cholesterol synthesis. To identify the principal site of inhibition in the cholesterolgenic pathway and the active components of garlic, cultured hepatoma cells were treated with aqueous garlic extract or its chemical derivatives, and radiolabeled cholesterol and intermediates were identified and quantified. Garlic extract reduced cholesterol synthesis by up to 75% without evidence of cellular toxicity. Levels of squalene and 2,3-oxidosqualene were not altered by garlic, indicating that the site of inhibition was downstream of lanosterol synthesis, and identical results were obtained with 14C-acetate and 14C-mevalonate, confirming that 3-hydroxy-3-methylglutaryl-CoA reductase activity was not affected in these short-term studies. Several methylsterols that accumulated in the presence of garlic were identified by coupled gas chromatography-mass spectrometry as 4,4'-dimethylzymosterol and a possible metabolite of 4-methylzymosterol; both are substrates for sterol 4alpha-methyl oxidase, pointing to this enzyme as the principal site of inhibition in the cholesterolgenic pathway by garlic. Of 9 garlic-derived compounds tested for their ability to inhibit cholesterol synthesis, only diallyl disulfide, diallyl trisulfide, and allyl mercaptan proved inhibitory, each yielding a pattern of sterol accumulation identical with that obtained with garlic extract. These results indicate that compounds containing an allyl-disulfide or allyl-sulfhydryl group are most likely responsible for the inhibition of cholesterol synthesis by garlic and that this inhibition is likely mediated at sterol 4alpha-methyl oxidase.