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Suppression of Mevalonate Pathway Activities by Dietary Isoprenoids: Protective Roles in Cancer and Cardiovascular Disease^1,2,

Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706

Diet-cancer and diet-cardiovascular disease interrelationships may be explained by the mevalonate-suppressive action of isoprenoid end products of plant secondary metabolism. Assorted monoterpenes, sesquiterpenes, carotenoids and tocotrienols posttranscriptionally down regulate 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, a key activity in the sterologenic pathway. The modest decrease in cholesterol synthesis is associated with a concomitant lowering of low-density lipoprotein cholesterol. The reductase activity in tumor tissues differs from that of liver in being resistant to sterol feedback regulation. Tumor reductase activity retains sensitivity to posttranscriptional regulation. As a consequence, the isoprenoid-mediated suppression of mevalonate synthesis depletes tumor tissues of two intermediate products, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are incorporated posttranslationally into growth control-associated proteins. At 10-fold higher concentrations, monoterpenes inhibit the protein isoprenyl transferases that catalyze this incorporation. At levels of intake likely provided by a diet based on Food Pyramid guidelines, assorted isoprenoids decrease cardiovascular disease risk and suppress the growth of initiated cells. At pharmacological levels of intake, isoprenoids block the initiation phase of chemical carcinogenesis. Isoprenoids targeted to the inhibition of the isoprenylation of oncogenic forms of ras proteins may offer a novel approach to chemotherapy. Adjunctive isoprenoids might decrease the level of competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase required to manage hypercholesterolemia.

KEY WORDS: • cancer • cardiovascular disease • dietary isoprenoids • mevalonate synthesis

¹ Presented as part of the symposium "Nutritional Modulation of Lipid-Mediated Signal Transduction Systems" given at Experimental Biology '94 meeting, Anaheim, CA, on April 26, 1994. This symposium was sponsored by the American Institute of Nutrition and supported by a grant from the Mead Johnson Corporation. Guest editor for this symposium was Alfred H. Merrill, Jr., Emory University School of Medicine, Atlanta, GA.

² Supported by PHS CA 49416 and University of Wisconsin-Madison College of Agricultural and Life Sciences, Madison.

³ To whom correspondence should be addressed: Department of Nutritional Sciences, 1415 Linden Drive, University of Wisconsin-Madison, Madison, WI 53706.

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