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-Hydroxylase and Other Xenobiotic Metabolism mRNA Are Upregulated by Soy Isoflavones1,2
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.
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ABSTRACT |
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 TOP ABSTRACT IntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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-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.
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Introduction |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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50% of hepatic cholesterol is converted into bile acids. This process is important for the removal of cholesterol from the body (1). Bile acids serve to emulsify dietary fat; 95% of luminal bile experiences enterohepatic circulation, a highly regulated and efficient process. The impairment of this pathway may result in severe hepatic disease (2). Hepatic drug and xenobiotic metabolism involves a coordinated response by phase I and II metabolizing enzymes and phase III transporters (3). Phase I hydroxylase enzymes are members of the cytochrome P450 (CYP)6 superfamily, including the CYP1, CYP2, and CYP3 subfamilies. After phase I hydroxylation, phase II enzyme action involves conjugation of substrate with hydrophilic groups. This conjugation allows for excretion of conjugates into bile or urine. Phase III drug transporters modulate the absorption, distribution, and excretion of drugs by the liver and intestine and regulate cellular concentrations of bile acids, xenobiotics, and drugs (4). Drug transporters may transport drugs, xenobiotics, and other lipids against the concentration gradient, utilizing the energy of ATP hydrolysis (5). The expression or activity of drug-metabolizing enzymes (DME) and transporters is subject to considerable polymorphic differences that complicate assessment of therapeutic treatments (6–8).
Enzymes from some CYP families play important roles in bile acid metabolism. Three members, CYP7A1, 8B1, and 27A1, are key enzymes for the bile acid biosynthetic pathway (9–11). There are 2 important bile acid synthesis pathways; the classic and acidic pathways. Action of both pathways explains the existence of multiple bile acid metabolites in human plasma (12).
DME and transporters are directly or indirectly regulated by the coordinated action of multiple nuclear receptors (13,14). The expression of different genes encoding enzymes of a common pathway may be coordinately controlled by similar transcription factors and cofactors (15). The action of 12--hydroxylase (CYP8B1) favors production of the more hydrophilic cholic acid (CA) over chenodeoxycholic acid (CDCA). Thus, the activity of CYP8B1 influences both the ratio of CA to CDCA and hydrophilicity of the bile acid pool (16). Multiple transcription factor binding sites have been identified on the promoter of CYP8B1 and peroxisome proliferator-activated receptor (PPAR), -fetoprotein transcription factor (FTF), and hepatocyte nuclear factor 4 (HNF4) may regulate CYP8B1 at overlapping response element sites (17–19). In addition, downregulation of CYP8B1 by sterols in an animal model has been attributed to sterol regulatory element binding proteins (20). Expression of CYP7A1, 27A1, and 8B1 is subject to inhibition by cholesterol, bile acids, and insulin; this inhibition may be due to the activation of small heterodimer partner (SHP), a universal repressor, by ligand-bound farnesoid x receptor (11).
Soy contains protein, lipids, fiber, and phytochemicals, such as isoflavones (21); although currently a matter of debate, in some studies, soy isoflavone intake has been associated with decreased blood cholesterol levels and improved blood lipoprotein profiles (22–24). Soy isoflavones may exert at least part of their lipid-regulating effect by modifying the activity of some lipid-regulating transcription factors, as shown by us and others (25–27). The regulation of DME and drug transporters by a variety of endogenous and exogenous compounds has been widely described and isoflavones have been shown as potential nuclear receptor ligands, thereby regulating expression of DME (28–30) and drug transporters (31,32).
To test the hypothesis that soy isoflavones induce the expression of hepatic CYP, the goal of this study was to identify human hepatic messenger RNA (mRNA) of xenobiotic metabolism that are regulated by soy isoflavones.
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Materials and Methods |
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(pcDNA1-rHNF4) were kindly donated by Dr. David Moore (Baylor College of Medicine, Houston, Texas). HNF4 is a highly conserved nuclear receptor in species from insect to human and the rat and human HNF4 expression plasmids do not differ (33). Primary human hepatocytes. Primary human hepatocytes were obtained through the Liver Tissue Procurement and Distribution System, Pittsburgh, PA (funded by NIH contract no. N01-DK-9-2310). Use of these cells was approved by the Institutional Review Board of the University of Notre Dame. Cells were cultured in serum-free Williams' E medium supplemented with 100 nmol/L dexamethasone and insulin-transferrin-selenium (ITS-G; Invitrogen). At 48 h after isolation, hepatocytes were treated with dimethyl sulfoxide + ethanol (D+E) as vehicle [0.1% (v:v)] or with the isoflavones genistein and daidzein at 40 µmol/L. In preliminary tests, equol was found to be a potent inducer of several CYP mRNA and 10 µmol/L provided a robust cellular response. Further, equol at 40 µmol/L apparently reduced cell viability whereas genistein and daidzein did not. Thus, we screened at 10 µmol/L for equol and 40 µmol/L for genistein and daidzein. Although these screening concentrations are somewhat higher than in vivo serum concentrations of isoflavones, the concentrations were chosen to produce robust induction levels; candidate mRNA obtained from this screen could then be later evaluated at lower, more physiological concentrations. Cells were cultured for a further 48 h before total RNA isolation using TRI Reagent (Sigma) according to the manufacturer's instructions. The concentration of RNA was determined using the SmartSpec 3000 spectrophotometer (BioRad); integrity of RNA was confirmed by evaluating 18S and 28S ribosomal RNA (rRNA) after RNA gel electrophoresis.
Mouse diet studies.
To evaluate the contribution of PPAR on CYP8B1 expression, PPAR-null and matched wild-type (wt) mice from a 129/Sv background were obtained from the Jackson Laboratory; 64 -null and 72 wt mice were used in the study. The animal protocol was approved by the institutional review board of the University of Notre Dame. All the mice had free access to water and food (Purina rodent diet no. 5015) until 11 wk of age. At 12 wk of age, we randomly divided the null and wt mice into 1 of 4 diet groups for each sex, and mice consumed a high-fat diet for 6 wk. We evaluated male and female mice separately. The experimental diets were: soy protein containing essentially no isoflavones (S); soy protein containing 1.82 mg isoflavones (aglycone form)/g protein (S+I); S plus 0.2% fenofibrate (S+F); and S+I plus 0.2% fenofibrate (S+I+F). Experimental diets are as in Mezei et al. (34) (Table 1). On the last day of wk 6, mice were killed and total RNA from liver was isolated following GenElute mammalian total RNA miniprep kit (Sigma).
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Plasmid construct for northern analysis. The forward primer for the CYP8B1 probe was 5'-CCTGTCCTTTGTAATGCGACGT-3' and the reverse primer was 5'- AGGGTTGAGGAAGCGATCGTA-3'. The RT-PCR product of the probe (795 bp) was cloned into the TOPO TA cloning vector for sequencing following the manufacturer protocol (Invitrogen) and the EcoRI-digested cDNA fragment from the plasmid was gel purified (Qiagen) and further used as probe.
Real time PCR.
Three micrograms of mouse liver total RNA was used to make first-strand cDNA with Maloney Murine Leukemia Virus (M-MLV) RT (Invitrogen) using random primers. RNA from every mouse was used to make independent cDNA samples. Real time PCR were performed with 1 µL cDNA using Sybr-green real time PCR Master mix (Applied Biosystems) in an ABI Prism 7700 sequence detector system (Applied Biosystems). The primers for mouse carnitine palmitoyltransferase 1 (Cpt1) (catalogue no. PPM25930A) and CYP8B1 (catalogue no. PPH01265A) were from Superarray and the sequence of mouse 18S primers was FWD-5'AGTCCCTGCCCTTTGTACACA3' and REV-5'GATCCGAGGGCCTCACTAAAC3'. Cycle threshold was plotted as separate standard curves and the final values of Cpt1 or CYP8B1 were normalized to 18S rRNA abundance in each sample.
HepG2 cell culture and transient transfections.
Human hepatoma HepG2 cells (ATCC) were maintained in minimal essential medium (MEM) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin (Invitrogen). Cells were maintained at 37°C, 5% CO2, and 100% relative humidity. Transient transfections were performed on 24-well plates. On d 1, cells were plated in MEM plus 10% serum. Cell medium was changed to serum-free MEM and cells were transfected using Lipofectamine 2000 (Invitrogen) on d 2. For transfecting 2 plasmids [CYP8B1-Luc and ß-galactosidase (gal) plasmids], 0.5 µg of each plasmid was used; for transfecting 3, 4, or 5 plasmids simultaneously (FTF, HNF4, PPAR, CYP8B1-Luc, and ß-gal plasmids), 0.3 µg of each plasmid was added to each well. The ß-gal plasmid was used as an internal control for transfection efficiency. Six hours after transfection, cell medium was replaced by fresh MEM. Twenty-four hours after adding plasmids to the cells, cells were exposed to the experimental conditions. All of the isoflavone treatments were prepared in 1000x stock dissolved in D+E and the final concentration of D+E in cell treatment medium was 0.1% (v:v). After the appropriate treatment period, HepG2 cells were lysed with 1x Reporter lysis buffer (Promega) and assays for Luc (Promega) and ß-gal (Promega) expression were performed. ß-Gal activity was measured at 420 nm (Bio-Tek Instruments). Luc activity was determined with LMax II 384 luminometer (Molecular Devices) and the ratio of Luc to ß-gal calculated. All transfection studies were repeated at least twice and each individual test involved independent triplicate measurements.
Statistical analysis.
One-way ANOVA and the Newman-Keuls multiple comparison test were used in the analysis of gene array data. Murine gene expression and all transfection experiments were analyzed by 1- or 2-way ANOVA where appropriate, followed by the Newman-Keuls post hoc multiple comparison test when the F test was significant at P 
0.05.
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Results |
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; the PPAR agonist WY-14,643 induced CYP8B1 mRNA and changed bile acid composition in wt mice. The absence of induction by the positive controls in PPAR-null mice indicated that the effect is through PPAR (18). Following this work, we used wt and PPAR-null mice to examine the in vivo effect of isoflavone consumption on CYP8B1 mRNA levels and to determine whether the upregulation of isoflavones on CYP8B1 is mediated by PPAR. The Cpt1 gene encodes the transporter responsible for uptake of fatty acids into the mitochondria; expression of the CPT1 mRNA is known to be primarily regulated by PPAR (35). As expected, we found CPT1 mRNA expression significantly increased in wt mice that had consumed fenofibrate, but this upregulation was completely abrogated in similarly fed PPAR-null mice (34). CYP8B1 mRNA levels increased by intake of isoflavones in both female and male mice. In contrast to PPAR regulation of CPT1 mRNA (18), consumption of PPAR agonist fenofibrate did not affect the expression of CYP8B1 to any degree. Interestingly, intake of soy isoflavones plus fenofibrate did not increase CYP8B1 mRNA levels in females, whereas there was an obvious upregulation in males (Table 3). Surprisingly, intake of isoflavones in a high-fat diet dramatically increased CYP8B1 mRNA levels in both female and male PPAR-null mice; consumption of the S+I+F diet significantly induced hepatic CYP8B1 mRNA levels in male but not in female mice (Table 3). The lack of PPAR resulted in a nearly 20-fold increase of CYP8B1 mRNA caused by intake of isoflavones in females and a nearly 10-fold increase in male mice fed either the S+I or S+I+F diet. Thus, the presence of PPAR attenuates isoflavone induction of CYP8B1 mRNA levels in 129/Sv mice fed a high-fat diet.
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and FTF were only weak regulators (17). However, cotransfection of HNF4 robustly increased basal CYP8B1 promoter activity. The addition of FTF with HNF4 did not change the dominant constitutive activity of HNF4 on CYP8B1. However, SHP, a universal inhibitor for several receptor-signaling pathways, markedly downregulated the transactivation of CYP8B1 by HNF4 (Table 5).
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, or PPAR, we exposed transfected HepG2 cells to the same concentration of individual isoflavones tested previously. Under the same experimental conditions, all 4 isoflavones produced a modest induction of CYP8B1-driven Luc with cotransfection of human FTF (Table 6). CYP8B1 reporter activity in cells cotransfected with HNF4 was induced by isoflavones, especially genistein, daidzein, and glycitein, but not equol (Table 6). Not surprisingly, there was no induction on CYP8B1 by isoflavone treatments in cells transfected with PPAR (Table 6). The inclusion of HNF4 dramatically upregulated the basal activity of CYP8B1; at least 3 different isoflavones induce the upregulation of CYP8B1 via HNF4 (Table 5).
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inhibits isoflavone upregulation of CYP8B1 in cotransfected HepG2 cells.
The absence of PPAR in PPAR-null mice resulted in the dramatic induction of CYP8B1 mRNA in isoflavone-fed mice. This suggested that normal expression of PPAR may have some inhibitory effect on the regulation of FTF and HNF4 on CYP8B1. To test this hypothesis, we cotransfected FTF and/or HNF4 with PPAR in transient transfection experiments and examined the effect of the exposure to genistein and daidzein on CYP8B1 reporter expression. The presence of PPAR prevented the induction of CYP8B1 by isoflavones. Interestingly, the presence of transfected FTF, HNF4, and PPAR dramatically decreased the basal activation of HNF4 on CYP8B1 (Table 7).
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Discussion |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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We first screened the expression of 96 target genes in drug metabolism pathways using primary human hepatocytes exposed to different isoflavones. We chose to expose human hepatocytes to higher concentrations of isoflavones than would be generally expected in vivo, electing to utilize these higher concentrations to maximize the possibility that robust differences would be observed, at least for some of the 96 different mRNA. We further evaluated expression levels at different isoflavone concentrations, including lower concentrations close to those expected in vivo (0.1–1 µmol/L). Our subsequent evaluation of CYP8B1 in this study illustrated the validity of this approach. It is worthy to note that despite the genetic, sex, and metabolic variability encountered because we used 4 different human donors for the gene screening project, we identified significant increases for 4 mRNA.
MDR1 is the best characterized MDR/ABC transporter and is universally expressed in most secretory cells. MRP2 is expressed exclusively in the canalicular (apical) membrane of the hepatocyte. Similar to other MDR, the substrates of MRP2 include some anticancer drugs; the overexpression of MDR and MRP proteins can confer drug resistance to cells (40,41). The induction of CYP1A1 and 3A4 in human hepatocytes exposed to isoflavones is similar to our prior findings that isoflavones upregulate the expression of CYP1A2 and 3A4 in transfected HepG2 cells and in primary human hepatocytes (data not shown). Two transferases, CHST5 and GSTT2, are phase II-conjugating enzymes whose mRNA were induced by isoflavones in our studies. Recent studies have demonstrated that the pregnane x receptor (PXR) and constitutive androstane receptor may bind with retinoid x receptor (RXR) as heterodimers to activate the transcription of MDR1 and MRP2 (42,43). Interestingly, studies of other phase II genes identify similar response elements in their promoter and enhancer regions and they are activated by multiple compounds via the aryl hydrocarbon receptor, constitutive androstane receptor, or PXR (44). We have found that isoflavones may serve as potential ligands for human aryl hydrocarbon receptor or PXR, binding to xenobiotic response elements to activate the transcription of CYP1A and 3A genes separately (data not shown). Therefore, it is not surprising to find that isoflavones may activate the transcription of other target genes through a similar pathway potentially mediated by PXR or other receptors.
The upregulation of CYP8B1 mRNA levels was observed in most of the donors used in the gene array study and in 3 additional donors evaluated via northern analysis (Fig. 2). The involvement of CYP8B1 in cholesterol and bile metabolism motivated us to study its regulation further. HepG2 cells and in vivo animal studies (Tables 3 and 4) suggest an interaction between dietary isoflavone levels and fenofibrate. Although with low dietary isoflavone intake the presence of fenofibrate did not affect 8B1 induction, the presence of fenofibrate significantly lowered 8B1 expression in 3 of the 4 cases when high levels of isoflavones were consumed (male and female in wt and knock-out (KO); Table 3). This interaction may be due to isoflavone activation of the PXR receptor. Inhibition of CYP7A1 gene expression by recirculated bile acids decreases the rate of conversion of cholesterol to bile acids and CDCA is the strongest inhibitor of CYP7A1 in all bile acids (45,46). When CYP8B1 is induced by isoflavones, there may be greater synthesis of the more hydrophilic CA rather than CDCA (Fig. 3A). If so, then during enterohepatic circulation, more of the hydrophilic, less inhibitory CA will be reabsorbed into hepatocytes, producing less transcriptional repression and greater activity of CYP7A1. This, in turn will lead to more bile acid synthesis and excretion into the intestine (Fig. 3A). This activation of CYP7A1 by isoflavones is consistent with other reports (47,48). Not surprisingly, the upregulation of CYP7A1 and 8B1 was associated with a decrease in plasma cholesterol levels in an animal study (49). From our study, the upregulation of CYP8B1 may help us explain at least in part a potential cholesterol-lowering effect of isoflavones. Other data from our laboratory demonstrate enhanced bile excretion in mice fed an isoflavone-containing diet (data not shown).
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, and PPAR on the induction of CYP8B1 by isoflavones (Table 6). FTF has been described as a weak regulator of CYP8B1 (17) with no known activating ligand. The slight increase in CYP8B1-Luc expression associated with cotransfection of FTF does not correspond to the robust increases observed in CYP8B1 mRNA levels. HNF4 is widely described as a constitutive, ligand-independent orphan receptor although fatty acids may be weak ligands of the receptor (50). Isoflavone-treated cells cotransfected with HNF4 produced a significant induction of CYP8B1, suggesting that isoflavones may serve to activate HNF4. In contrast to FTF and HNF4, cotransfection of PPAR abrogates the upregulation of CYP8B1 produced by exposure to isoflavones (Table 6).
Studies in PPAR-null mice showed unexpectedly robust increases in CYP8B1 mRNA levels after intake of isoflavones, suggesting an inhibitory role of PPAR on the regulation of the CYP8B1 gene (Table 3). In our transfected cell model, we observed a lack of induction of CYP8B1 by isoflavones when PPAR was cotransfected with other transcription factors. Interestingly, the coexpression of PPAR with FTF and HNF4 significantly decreased the constitutive action of HNF4 on CYP8B1 in the transfected cell model (Table 7). This effect is consistent with other findings showing PPAR/RXR significantly reduced HNF4 expression in HepG2 cells (51,52). To summarize the effect of isoflavones on CYP8B1 regulation, summary models provide an overview of bile synthesis and recirculation and transcriptional activation of the CYP8B1 gene promoter (Fig. 3B).
In this study, we found that isoflavones were able to induce the transcription of CYP8B1 and we hypothesized the subsequent changes of CYP8B1 upregulation on bile acid pathway. Our findings regarding potential agonists for CYP8B1 gene expression are novel in contrast to previous reports identifying several antagonists for CYP8B1, such as bile acids, cholesterol, and inflammatory cytokines (53). Changes in CYP8B1 activity will lead to altered ratios of primary bile acids CA and CDCA (Fig. 3A).
Contrary to a previous finding about the active regulation of PPAR on CYP8B1 (18), our data showed a prominent lack of activation of CYP8B1 by PPAR; indeed, PPAR was even shown to play an inhibitory role. In contrast to the prior study, we used a very high-fat diet fed for 6 wk to assess the ability of isoflavones to reduce serum and tissue lipid levels and to determine whether this phenomenon occurred via a PPAR-dependent pathway (34). Although cholesterol feeding of mice and rats has been shown to decrease the activity of CYP8B1 (54), we observed the upregulation of CYP8B1 with isoflavone intake. This upregulation was not similarly related to intake of the PPAR agonist, fenofibrate. These data indicate that PPAR may work as a weak transcription activator, a conclusion similar to another study (17).
In conclusion, this study demonstrates that isoflavones induce expression of several important genes of drug metabolism pathways in human hepatocytes; a notable target is CYP8B1. The mechanism producing this induction further clarifies the roles of different nuclear receptors on CYP8B1 regulation and demonstrates that HNF4 is, at present, one likely candidate mediating the effect of isoflavones on CYP8B1. Our model helps explain a potential hypolipidemic role of isoflavones and the interaction of PPAR with other transcription factors on the regulation of bile acid synthesis.
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FOOTNOTES |
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2 Author disclosures: Y. Li, O. Mezei, and N. F. Shay, no conflicts of interest.
3 Present address: Department of Pathology, Wayne State University, 111 Lande Building, 550 E. Canfield, Detroit, MI 48201 (yilanli{at}med.wayne.edu).
4 Present address: Baylor College of Medicine, 1100 Bates Street, Houston, TX 77030.
5 Present address: WK Kellogg Institute for Food and Nutrition Research, 2 Hamblin Avenue, Battle Creek, MI 49017 (neil.shay{at}kellogg.com).
6 Abbreviations used: CA, cholic acid; CDCA, chenodeoxycholic acid; CHST5, carbohydrate sulfotransferase-5; Cpt1, carnitine palmitoyltransferase 1; CYP, cytochrome P450; CYP8B1, 12--hydroxylase; DME, drug-metabolizing enzyme; D+E, dimethyl sulfoxide + ethanol; FTF, -fetoprotein transcription factor; gal, galactosidase; GSTT2, glutathione-sulfotransferase-2; HNF4, hepatocyte nuclear factor 4; KO, knock-out; Luc, luciferase; MDR1, Multi-drug restistant-1; MEM, minimal essential medium; mRNA, messenger RNA; MRP2, Multidrug-related protein-2; PPAR, peroxisome proliferator-activated receptor ; PXR, pregnane x receptor; rRNA, ribosomal RNA; S, soy protein diet containing essentially no isoflavones; S+F, soy protein diet containing essentially no isoflavones plus 0.2% fenofibrate; SHP, small heterodimer partner; S+I, soy protein diet containing 1.82 mg isoflavones (aglycone form)/g protein; S+I+F, soy protein diet containing 1.82 mg isoflavones (aglycone form)/g protein plus 0.2% fenofibrate; wt, wild-type.
Manuscript received 30 August 2006. Initial review completed 19 October 2006. Revision accepted 11 April 2007.
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