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Biochemical, Molecular, and Genetic Mechanisms

Human and Murine Hepatic Sterol-12--Hydroxylase and Other Xenobiotic Metabolism mRNA Are Upregulated by Soy Isoflavones^1,2

Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556

^* To whom correspondence should be addressed. E-mail: neil.shay{at}kellogg.com.

The transport and metabolism of xenobiotics is controlled by the drug transporters and drug-metabolizing enzymes in the liver and small intestine. Expression of these genes is 1 factor affecting the half-life of drugs and xenobiotics. Isoflavone-containing soyfood products and supplements are promoted to treat several different health conditions, including improvement of blood lipid profiles. Because relatively high isoflavone intake may be possible via use of supplements, we tested the hypothesis that isoflavones regulate the expression of genes critical to drug transport and metabolism. Using a gene array screening method, 2 drug transporters, Multidrug restistant-1 and Multidrug-related protein-2; 3 phase I enzymes, cytochrome 1A1, 3A4, and 8B1; and 2 phase II enzymes, carbohydrate sulfotransferase-5 and glutathione-sulfotransferase-2, were upregulated 3-fold or more of the initial expression levels in primary human hepatocytes exposed to soy isoflavones for 48 h. Isoflavone-related induction of 12--hydroxylase (CYP8B1) was further studied in other in vitro and murine in vivo models. Transfection studies suggest that isoflavones may act as a weak activating ligand for hepatocyte nuclear factor 4, which in turn may activate the transcription of CYP8B1. The action of soy isoflavones on CYP8B1 may increase the conversion of cholesterol into bile acids and enhance synthesis of cholic acid. These isoflavone-induced changes in gene expression may help explain how isoflavones modulate cholesterol metabolism.