Effects of prior oral contraceptive use and soy isoflavonoids on estrogen-metabolizing cytochrome P450 enzymes

Abstract

Estrogen exposure and metabolism may play an important role in the development of estrogensensitive cancers in postmenopausal women. In this study we investigated whether past oral contraceptive (OC) administration or current dietary isoflavonoids (IF) affected expression and/or activity of steroid hormone-metabolizing cytochrome P450 (CYP) enzymes using complementary primate and cell culture models. One-hundred-eighty-one female cynomolgus macaques were randomized to receive OC or nothing for 26 months premenopausally, then ovariectomized and randomized to one of three diets for 36 months: an IF-depleted soy protein isolate (Soy−) diet, a Soy diet with IF (Soy+), or a Soy− diet supplemented with conjugated equine estrogens (CEE). Prior OCtreatment significantly reduced CYP gene expression in the mammary gland (≤60% of OC−). Dietary IFs had no effect on CYP expression, while CEE-treatment decreased CYP1A1 and increased CYP3A4 mRNA in a tissue-specific manner. For in vitro studies, we measured effects of the isoflavonoids genistein, daidzein and equol on CYP activity using intact V79 cells stably transfected to express CYP1A1, CYP1B1, or CYP3A4. All three IFs significantly altered CYP activity in a dosedependent and isoform-specific manner (20-95% inhibition vs. controls). These results suggest potential mechanisms for prior OC and dietary IF effects on cancer risk in estrogen-responsive tissues.

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

“…In contrast, no differences were observed in inducibility of CYP1A1 and CYP1B1 in the uterus of female rats fed casein or SPI and treated with DMBA (Ronis et al 2016). Also in contrast to data in rats, no significant change in expression of CYP1A1 or CP1B1 was observed in the mammary gland of ovariectomized female cynomolgus macaques fed soy diets with or without bound phytochemicals for 36 months (Scott et al 2008). …”

“…Genistein was also reported to inhibit recombinant human CYP1A1 and CYP1B1 activity at lower Ki of 15 and 0.7 μM respectively wheras daidzein was ineffective (Chan and Leung, 2003). In contrast, genistein, daidzein and the daidzein metabolite equol were all shown to be dose-dependent CYP1A1 and CYP1B1 inhibitors in transfected V79 cells at concentrations from 3–30 μM (Scott et al, 2008). In H411E rat hepatoma cell cultures genistein and daidzein were both reported to inhibit induction of CYP1A1 by omeprazole which activates the AhR/ARNT complex without AhR binding.…”

Soy Intake is Associated with Increased 2-Hydroxylation and Decreased 16α-Hydroxylation of Estrogens in Asian-American Women

“…Isoflavones can affect enzyme activity directly through competitive inhibition or indirectly, through interactions with receptors that induce enzyme expression (38). In vitro studies suggest that exposure to soy isoflavones can modulate both expression and activity of several of these enzymes, however the net effects of soy exposure on estrogen metabolism in vivo remain unclear (39, 40). …”

Effects of caffeine, tea polyphenol and daidzein on the pharmacokinetics of lansoprazole and its metabolites in rats

“…The consumption of fermented soybean products is gradually increasing around the world, due to their various health benefits (Kim et al, 2010). Genistein, flavones and isoflavones in soy can inhibit the activity of CYP3A4 (Scott et al, 2008). High-content daidzein, which is a soy isoflavone, has been detected in celery and arrowroot.…”