Feeding soy diets has been shown to induce cytochrome P450s in gene family CYP3A in Sprague-Dawley rat liver. We compared expression of CYP3A enzymes on postnatal Day 33 (PND33) rats fed casein or soy protein isolate (SPI+)–based AIN-93G diets continuously from gestational Day 4 through PND33 or the diets were switched on PND15 (n = 3–6 litters) to examine the potential imprinting effects of soy on drug metabolism. In addition rats were fed casein, SPI+, SPI+ stripped of phytochemicals (SPI–), or casein diets supplemented with the soy-associated isoflavones genistein or daidzein from weaning through PND33 to examine the hypothesis that the isoflavones are responsible for CYP3A induction by soy feeding. Feeding SPI either continuously or from weaning induced hepatic CYP3A1 and CYP3A2 mRNA, apoprotein, and CYP3A-dependent testosterone 6β-hydroxylase activity in liver microsomes 2- to 5-fold (P < 0.05). CYP3A mRNA expression was also elevated 2- to 3-fold in the jejunum of SPI-fed rats (P < 0.05). CYP3A was not induced in livers of rats switched to casein from soy at weaning. Induction of CYP3A1 also did not occur in rats fed SPI–, but CYP3A2 mRNA and apoprotein were induced (P < 0.05) in females fed SPI–. Offspring weaned onto genistein-supplemented diets had no elevation of CYP3A mRNAs or apoproteins. Weaning onto daidzein diets increased CYP3A2 mRNA and apoprotein expression in male rats (P < 0.05). These data suggest that early soy consumption may increase the metabolism of a wide variety of CYP3A substrates, but that soy does not imprint the expression of CYP3A enzymes. Effects on CYP3A1 expression appear to be primarily due to phytochemical components of SPI other than isoflavones. In contrast, consumption of soy protein and daidzein appear to be associated with the induction of CYP3A2.

CYP3A

10.1177/153537020623100107

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Feeding soy protein isolate and treatment with estradiol have different effects on mammary gland morphology and gene expression in weanling male and female rats

Physiological Genomics (2013)

Isabelle R. Miousse Neha Sharma Michael L. Blackburn Jamie Vantrease Horacio Gomez‐Acevedo

Isoflavones are phytochemical components of soy diets that bind weakly to estrogen receptors (ERs). To study potential estrogen-like actions of soy in the mammary gland during early development, we fed weanling male and female Sprague-Dawley rats a semipurified diet with casein as the sole protein source from postnatal day 21 to 33, the same diet substituting soy protein isolate (SPI) for casein, or the casein diet supplemented with estradiol (E2) at 10 μg/kg/day. In contrast to E2, the SPI diet induced no significant change in mammary morphology. In males, there were 34 genes for which expression was changed ≥2-fold in the SPI group vs. 509 changed significantly by E2, and 8 vs. 174 genes in females. Nearly half of SPI-responsive genes in males were also E2 responsive, including adipogenic genes. Serum insulin was found to be decreased by the SPI diet in males. SPI and E2 both downregulated the expression of ERα ( Esr1) in males and females, and ERβ ( Esr2) only in males. Chromatin immunoprecipitation revealed an increased binding of ERα to the promoter of the progesterone receptor ( Pgr) and Esr1 in both SPI- and E2-treated males compared with the casein group but differential recruitment of ERβ. ER promoter binding did not correlate with differences in Pgr mRNA expression. This suggests that SPI fails to recruit appropriate co-activators at E2-inducible genes. Our results indicate that SPI behaves like a selective estrogen receptor modulator rather than a weak estrogen in the developing mammary gland.

Weanling

Estrogen receptor alpha

Chromatin immunoprecipitation

10.1152/physiolgenomics.00096.2013

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Data from Alcohol Consumption Promotes Diethylnitrosamine-Induced Hepatocarcinogenesis in Male Mice through Activation of the Wnt/β-Catenin Signaling Pathway

Kelly E. Mercer Leah Hennings Neha Sharma Keith Lai Mario A. Cleves

<div>AbstractAlthough alcohol effects within the liver have been extensively studied, the complex mechanisms by which alcohol causes liver cancer are not well understood. It has been suggested that ethanol (EtOH) metabolism promotes tumor growth by increasing hepatocyte proliferation. In this study, we developed a mouse model of tumor promotion by chronic EtOH consumption in which EtOH feeding began 46 days after injection of the chemical carcinogen diethylnitrosamine (DEN) and continued for 16 weeks. With a final EtOH concentration of 28% of total calories, we observed a significant increase in the total number of preneoplastic foci and liver tumors per mouse in the EtOH+DEN group compared with corresponding pair-fed (PF)+DEN and chow+DEN control groups. We also observed a 4-fold increase in hepatocyte proliferation (P < 0.05) and increased cytoplasmic staining of active-β-catenin in nontumor liver sections from EtOH+DEN mice compared with PF+DEN controls. In a rat model of alcohol-induced liver disease, we found increased hepatocyte proliferation (P < 0.05); depletion of retinol and retinoic acid stores (P < 0.05); increased expression of cytosolic and nuclear expression of β-catenin (P < 0.05) and phosphorylated-glycogen synthase kinase 3β (p-GSK3β), P < 0.05; significant upregulation in Wnt7a mRNA expression; and increased expression of several β-catenin targets, including, glutamine synthetase (GS), cyclin D1, Wnt1 inducible signaling pathways protein (WISP1), and matrix metalloproteinase-7(MMP7), P < 0.05. These data suggest that chronic EtOH consumption activates the Wnt/β-catenin signaling pathways to increase hepatocyte proliferation, thus promoting tumorigenesis following an initiating insult to the liver. Cancer Prev Res; 7(7); 675–85. ©2014 AACR.</div>

Consumption

10.1158/1940-6207.c.6544473.v1

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Isoflavone Conjugates Are Underestimated in Tissues Using Enzymatic Hydrolysis

Journal of Agricultural and Food Chemistry (2005)

Liwei Gu Myriam Laly Hebron C. Chang Ronald L. Prior Nianbai Fang

Many health effects of soy foods are attributed to isoflavones. Isoflavones upon absorption present as free form, glucuronide, and sulfate conjugates in blood, urine, and bile. Little is known about the molecular forms and the relative concentrations of soy isoflavones in target organs. Acid hydrolysis or enzymatic hydrolysis (glucuronidases and sulfatases) was used to study isoflavone contents in the heart, brain, epididymis, fat, lung, testis, liver, pituitary gland, prostate gland, mammary glands, uterus, and kidney from rats fed diets made with soy protein isolate. The heart had the lowest isoflavone contents (undetectable), and the kidney had the highest (1.8 ± 0.6 nmol/g total genistein; 3.0 ± 1.1 nmol/g total daidzein). Acid hydrolysis released 20−60% more aglycon in tissues than enzymatic digestion (p < 0.05), and both hydrolysis methods gave the same level of isoflavones in serum. Approximately 28−44% of the total isoflavone content within the liver was unconjugated aglycon, and the remainder was conjugated mainly as glucuronide. The subcellular distribution of total isoflavones was 55−60% cytosolic and 13−16% in each of the nuclear, mitochondrial, and microsomal fractions. These results demonstrated that (1) soy isoflavones distribute in a wide variety of tissues as aglycon and conjugates and (2) the concentrations of isoflavone aglycons, which are thought to be the bioactive molecules, are in the 0.2−0.25 nmol/g range, far below the concentrations required for most in vitro effects of genistein or daidzein. Keywords: Isoflavones; daidzein; genistein; tissues

Enzymatic Hydrolysis

10.1021/jf050802j

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Effects of soy containing diet and isoflavones on cytochrome P450 enzyme expression and activity

Drug Metabolism Reviews (2016)

Martin J. J. Ronis

Cytochromes P450 (CYPs) play an important role in metabolism and clearance of most clinically utilized drugs and other xenobiotics. They are important in metabolism of endogenous compounds including fatty acids, sterols, steroids and lipid-soluble vitamins. Dietary factors such as phytochemicals are capable of affecting CYP expression and activity, which may be important in diet-drug interactions and in the development of fatty liver disease, cardiovascular disease and cancer. One important diet-CYP interaction is with diets containing plant proteins, particularly soy protein. Soy diets are traditionally consumed in Asian countries and are linked to lower incidence of several cancers and of cardiovascular disease in Asian populations. Soy is also an important protein source in vegetarian and vegan diets and the sole protein source in soy infant formulas. Recent studies suggest that consumption of soy can inhibit induction of CY1 enzymes by polycyclic aromatic hydrocarbons (PAHs) which may contribute to cancer prevention. In addition, there are data to suggest that soy components promiscuously activate several nuclear receptors including PXR, PPAR and LXR resulting in increased expression of CYP3As, CYP4As and CYPs involved in metabolism of cholesterol to bile acids. Such soy-CYP interactions may alter drug pharmacokinetics and therapeutic efficacy and are associated with improved lipid homeostasis and reduced risk of cardiovascular disease. The current review summarizes results from in vitro; in vivo and clinical studies of soy-CYP interactions and examines the evidence linking the effects of soy diets on CYP expression to isoflavone phytoestrogens, particularly, genistein and daidzein that are associated with soy protein.

Pregnane X receptor

CYP1B1

10.1080/03602532.2016.1206562

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Citations (58)

Cyclic Expression of Class I Alcohol Dehydrogenase in Male Rats Treated with Ethanol

Biochemical and Biophysical Research Communications (2000)

Thomas M. Badger Jan‐Olov Höög Stefan P. Svensson Robert E. McGehee Che Fang

Ethanol metabolism

10.1006/bbrc.2000.3186

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Citations (36)