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Biochemical and Molecular Actions of Nutrients

S-Alk(en)yl Cysteines of Garlic Inhibit Cholesterol Synthesis by Deactivating HMG-CoA Reductase in Cultured Rat Hepatocytes¹

Nutrition Department, The Pennsylvania State University, University Park, PA 16802

²To whom correspondence should be addressed. E-mail: yyy1{at}psu.edu.

The effects of water-soluble organosulfur compounds of garlic on hepatic cholesterol biosynthesis in cultured rat hepatocytes were studied. S-Alk(en)yl cysteines, i.e., S-allyl cysteine (SAC), S-ethyl cysteine (SEC) and S-propyl cysteine (SPC) inhibited cholesterol synthesis from [¹⁴C]acetate but not from [¹⁴C]mevalonate. The activity of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase in the cells treated with SAC, SEC and SPC was 30–40% lower than that of the untreated cells. S-Alk(en)yl cysteines did not alter abundance of mRNA coded for HMG-CoA reductase or protein concentration of the enzyme. The ratio of expressed to total activity (E/T) of HMG-CoA reductase was then determined as an index of phosphorylation status of the enzyme. The E/T ratio was reduced 18–29% by SAC, SEC and SPC, resulting primarily from decreased expressed activity. The results suggest that S-alk(en)yl cysteines inhibit cholesterol synthesis by deactivating HMG-CoA reductase via enhanced phosphorylation, but not changing levels of mRNA or the amount of the enzyme. Additionally, of the three S-alk(en)yl cysteines tested, only SAC appears to further decrease the activity of HMG-CoA reductase by increasing sulfhydryl oxidation of the enzyme.

KEY WORDS: • garlic • hepatocytes • HMG-CoA reductase • S-alk(en)yl cysteines

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