Botanical-Drug Interactions: Soy Isoflavones and Drug Metabolism

Atherosclerosis is one of the leading causes of mortality and morbidity in western countries and high total cholesterol and high low-density lipoprotein (LDL) cholesterol levels are associated with the development of atherosclerosis. Soy intake has been documented to reduce the risk of heart disease by lowering blood cholesterol levels. Isoflavone-containing soyfood products and supplements are commercially available and promoted to treat several different health conditions including improving blood lipid profiles. The transport and metabolism of most xenobiotics are affected by the drug transporters and metabolizing enzymes in the liver and small intestine and the expression of these genes affect the potency of drugs or xenobiotics. Cytochrome P450s (CYPs) are important phase I drug-metabolizing enzymes in the liver and the expression levels of CYP1, 2, and 3 subfamilies are the rate-limiting factor for the turnover of many drugs. The cholesterol-lowering statins may be metabolized by different CYPs. Among the isoforms, CYP3A4 is responsible for nearly 54% of all drug-turnover and is considered most important. There is evidence showing that soy isoflavones may affect the expression of some of the genes in drug metabolism pathways. My project is focused on the effect of isoflavones on CYP1A2, 2C9, 3A4, as model isoforms of CYPs, and the identification of other genes pertaining to drug transport and biotransformation whose expression is affected by isoflavones. We have found that isoflavones upregulate CYP3A4 expression; and equol, a metabolite of daidzein, appears to be a most potent inducer of CYP3A4. Similarly, isoflavones also induce the expression of CYP1A2, but not CYP2C9. Using gene screening methods, two drug transporters, three phase I enzymes, and two phase II enzymes were identified to be induced by isoflavones in human hepatocytes exposed to isoflavones. CYP8B1, a gene encoding an enzyme at a branch point in the bile acid synthesis pathway appears to be an important target gene activated by isoflavones. Furthermore, an interaction between isoflavones and statins appears to affect CYP3A4 gene transcription and cellular lipid metabolism. Taken together, the isoflavones are able to affect the complex drug metabolism pathways and these in-vitro interactions of isoflavones with statins suggest clinical studies are warranted.