The Effect of Soy Isoflavones on Nucleotide, Lipid and Drug Metabolism

Coronary heart disease is the leading cause of mortality in the U.S. and other western countries. Two risk factors for development of this disease are elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels. Therapies for highly elevated cholesterol levels generally include dietary modification and pharmaceutical treatment. Soy consumption lowers TC and LDL-C; replacing animal protein sources with soy protein in the diet is a suggested dietary modification to improve cholesterol profiles. However, the mechanism by which soy improves cholesterol profiles is unknown. We hypothesize that consumption of soy isoflavones can alter gene expression in human and rodent models, and that this may be one mechanism by which soy lowers cholesterol.

In addition to dietary modification, some individuals augment their diet with soy extract supplements. Some dietary supplements have been demonstrated to alter the effectiveness of conventional drugs. Since lipid- and cholesterol-lowering drugs are often prescribed concurrently with dietary modification, we are interested in elucidating potential interactions of soy isoflavones with prescription drugs. We have shown that mice consuming a diet containing both a triglyceride-lowering drug (fenofibrate) and soy isoflavones had lower serum and urinary and higher fecal fenofibrate concentrations than mice consuming a diet without isoflavones. Additionally, genes critical to the bile synthesis pathway were identified in this work to be induced in mice consuming an isoflavone-containing diet. Mice consuming a diet high in isoflavones demonstrated increased mRNA levels of cyp7a1 and cyp27a1 (the rate-limiting steps of the classic and alternative bile acid synthetic pathways, respectively), as well as decreased mRNA levels of asbt (a transporter which recovers bile acids back into enterohepatic recirculation). The outcome of these changes would be a decrease in recovered bile acids and a resulting increase in conversion of cholesterol to keep the bile acid pool in homeostasis. Serum total bile acids decreased in keeping with the mRNA changes. We also found that the effects were greatest when cholesterol was provided in the diet. Taken together, the isoflavones are able to affect gene expression in the bile synthetic pathway as well as alter the disposition of a lipid-lowering drug.