SUPPRESSION OF MEVALONATE PATHWAY ACTIVITIES BY DIETARY ISOPRENOIDS -PROTECTIVE ROLES IN CANCER AND CARDIOVASCULAR-DISEASE

Diet-cancer and diet-cardiovascular disease interrelationships may be explained by the mevalonate-suppressive action of isoprenoid end produ cts of plant secondary metabolism. Assorted monoterpenes, sesquiterpen es, carotenoids and tocotrienols posttranscriptionally down regulate 3 -hydroxy-3-methylglutaryl coenzyme A reductase activity, a key activit y in the sterologenic pathway. The modest decrease in cholesterol synt hesis is associated with a concomitant lowering of low-density lipopro tein 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 regulat ion. As a consequence, the isoprenoid-mediated suppression of mevalona te synthesis depletes tumor tissues of two intermediate products, farn esyl pyrophosphate and geranylgeranyl pyrophosphate, which are incorpo rated posttranslationally into growth control-associated proteins. At 10-fold higher concentrations, monoterpenes inhibit the protein isopre nyl 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 grow th of initiated cells. At pharmacological levels of intake, isoprenoid s block the initiation phase of chemical carcinogenesis. Isoprenoids t argeted to the inhibition of the isoprenylation of oncogenic forms of ras proteins may offer a novel approach to chemotherapy. Adjunctive is oprenoids might decrease the level of competitive inhibitors of 3-hydr oxy-3-methylglutaryl coenzyme A reductase required to manage hyperchol esterolemia.