Human and Murine Hepatic Sterol-12-α-Hydroxylase and Other Xenobiotic Metabolism mRNA Are Upregulated by Soy Isoflavones

Abstract

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-alpha-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 4alpha, 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.

Human CYP3A4 and Murine Cyp3A11 Are Regulated by Equol and Genistein via the Pregnane X Receptor in a Species-Specific Manner

“…To assess the effect on the full-length human CYP3A4 promoter, HepG2 cells were transfected using Lipofectamine 2000 (Invitrogen) as previously described (27). Typically, transfections included 300 ng of wild-type hPXR, 300 ng of the CYP3A4-luciferase reporter, and an equal amount of pSV-bgalactosidase plasmid as the internal control.…”

“…Primary human hepatocytes were plated in medium without serum for 48 h and then incubated with different treatments for a further 48 h. After the treatment period, cells were lysed, protein was isolated, and protein concentrations were determined using a DC protein assay (BioRad). Immunoblotting was performed as previously described (27) using anti-human CYP3A4 (5/7) and anti-b-actin antibodies (Chemicon). The enhanced chemiluminescence-plus chemiluminescent detection system (Amersham) was used to identify the proteins of interest and quantification of the relative amount of protein/band was determined by densitometric scanning and analysis using the Quantity One System (BioRad).…”

“…002448) were housed under standard conditions and consumed food (Purina rodent diet no. 5015) (27,29) and water ad libitum. Experimental procedures were approved by the local Committee for Care and Use of Laboratory Animals at the University of Notre Dame.…”

Drug–Nutrient Interactions: A Broad View with Implications for Practice

“…As mentioned previously, many of the dietary polyphenols and other phytochemicals increasingly found in supplement products are substrates for-or influence expression and activity of-transporters and drug metabolizing enzymes (106)(107)(108)(109)(110)(111)(112)(113)(114). For example, soy isoflavones (eg, daidzein, genistein) can substantially upregulate two drug transporters and five enzymes (27,115). Even specific probiotic strains can play a role in altering transporter function responsible for drug and nutrient absorption (116).…”

Phytase: An Enzyme to Improve Soybean Nutrition

“…Another new finding is the ability of soy isoflavones to up-regulate the expression of genes critical for drug transport and metabolism. Of especial interest is the stimulation of several phase I and II metabolizing enzymes that may act in the chemoprevention of cancer, or the activation of CYP family of enzymes that play an important role in bile acid metabolism (Appelt & Reicks, 1997;Li et al, 2007;Bolling & Parkin, 2008). Therefore, it will be fascinating to explore potential synergism between phytase and soybean in improving human and animal health beyond nutrition.…”