Garlic and garlic-derived compounds inhibit human squalene monooxygenase

Although extracts of garlic inhibit cholesterol biosynthesis in cultured he patocytes, the inhibitory components of garlic and the site or sites of inh ibition in the cholesterol biosynthetic pathway have not been established. To elucidate potential mechanisms of inhibition, we examined the effect of fresh garlic extract and 16 water- or lipid-soluble compounds derived from garlic on purified recombinant human squalene monooxygenase. Squalene monoo xygenase catalyzes the second and likely rate-limiting step in the downstre am pathway for cholesterol biosynthesis. A 50% inhibitory concentration (IC 50) of squalene epoxidation was achieved with 1 g/L of fresh garlic extract ; of the 16 garlic compounds tested, only selenocystine (IC50 = 65 mu mol/L ), S-allylcysteine (IC50 = 110 mu mol/L), alliin (IC50 = 120 mu mol/L), dia llyl trisulfide (IC50 = 195 mu mol/L), and diallyl disulfide (IC50 = 400 mu mol/L) substantially inhibited the enzyme. Kinetic analysis showed that th e inhibition by garlic and by these compounds was slow and irreversible, su ggestive of covalent binding to the enzyme; the ability of thiol-containing compounds such as glutathione and 2,3-dimercaptopropanol to prevent and re verse the inhibition indicated that the garlic compounds were reacting with sulfhydryl groups on the protein. Dithiols were better reversal agents tha n monothiols, further suggesting that these inhibitors bind to the proposed vicinal sulfhydryls present on this enzyme. These results indicate that sq ualene monooxygenase may be one of the target enzymes through which garlic inhibits cholesterol biosynthesis.