Ce. Elson, SUPPRESSION OF MEVALONATE PATHWAY ACTIVITIES BY DIETARY ISOPRENOIDS -PROTECTIVE ROLES IN CANCER AND CARDIOVASCULAR-DISEASE, The Journal of nutrition, 125(6), 1995, pp. 1666-1672
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.