Estradiol induces cytochrome P450 2B6 expression at high concentrations: Implication in estrogen-mediated gene regulation in pregnancy

Koh, Kyung Bong; Jurkovic, Steve; Yang, Kunlun; Choi, Sang Hyoun; Jung, Jin Woo; Kim, Kwang Pyo; Zhang, Wei; Jeong, Hyunyoung

doi:10.1016/j.bcp.2012.03.016

Cited by 54 publications

(57 citation statements)

References 42 publications

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“…This lack of effect may be attributable to rapid depletion of these steroids from the incubation medium as previously reported (Choi et al, 2013). In their study, even when the medium was changed frequently to compensate for this depletion, estradiol or progesterone, at the 10Â total third trimester plasma concentrations, resulted in a maximum 3-fold induction of CYP3A activity in some SCHHs (Choi et al, 2013;Koh et al, 2012). Moreover administration of medroxyprogesterone acetate to postmenopausal women results in a modest increase (23-25%) in in vivo CYP3A activity, as determined by prednisolone clearance (Tsunoda et al, 1998).…”

Section: Discussionmentioning

confidence: 54%

Induction of Hepatic CYP3A Enzymes by Pregnancy-Related Hormones: Studies in Human Hepatocytes and Hepatic Cell Lines

Papageorgiou

Grepper

Unadkat

2013

Drug Metabolism and Disposition

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CYP3A activity is induced by approximately 2-fold during the third trimester of human pregnancy. Placental growth hormone (PGH), estrogens (primarily 17b-estradiol), cortisol, and progesterone have the potential to modulate CYP3A activity. Therefore, we determined whether the elevated plasma concentrations of these hormones during pregnancy induce hepatic CYP3A expression. We incubated sandwich-cultured human hepatocytes (SCHH) from premenopausal female donors (n = 2) with the physiologic (unbound, 13 total) and the 103 total third trimester hormone plasma concentrations (individually and in combination) and determined their effect on CYP3A activity and the transcripts of CYP3A4, CYP3A5, and the respective hormone receptors (growth hormone receptor, glucocorticoid receptor, and estrogen receptor alpha). Of all the hormones, cortisol was the most potent inducer of CYP3A activity and CYP3A4, CYP3A5 mRNA expression. The combination of PGH/growth hormone and cortisol induced CYP3A activity and expression significantly more than did cortisol alone. When incubated with the unbound or total plasma concentration of all the hormones, CYP3A activity in SCHH was induced to an extent comparable to that observed in vivo during the third trimester. These hormones had only a modest effect on the mRNA expression of the hormone receptors. The pattern of induction observed in SCHH was reproduced in HepaRG cells but not in HuH7/ HepG2 cells. SCHH or HepaRG cells could be used to determine the mechanistic basis of CYP3A induction during pregnancy and to predict the magnitude of induction likely to be observed during the first and second trimesters, when phenotyping studies to measure in vivo CYP3A activity are logistically difficult to perform.

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Section: Discussionmentioning

confidence: 54%

Induction of Hepatic CYP3A Enzymes by Pregnancy-Related Hormones: Studies in Human Hepatocytes and Hepatic Cell Lines

Papageorgiou

Grepper

Unadkat

2013

Drug Metabolism and Disposition

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“…This appears to suggest that differential regulatory mechanisms may play a role in the hormonal action on P450 expression. Indeed, we and other groups have reported that estradiol is an activator of human CAR (but not of PXR), whereas progesterone is an activator of PXR (but not of CAR) at concentrations reached during pregnancy (Lehmann et al, 1998;Jeong et al, 2008;Koh et al, 2012). Expectedly, estradiol-activated ERa would also play a role in the differential actions of estradiol and progesterone on P450 expression; CYP2A6 and CYP2B6 are known targets of ERa (Higashi et al, 2007;Lo et al, 2010;Koh et al, 2012).…”

Section: Discussionmentioning

confidence: 82%

“…In MCF-7 (human breast cancer) and HepG2 (human hepatoma) cells, estradiol is shown to enhance expression of CYP2A6 and CYP2B6 while decreasing CYP2C19 expression by activating estrogen receptor a (ERa) (Higashi et al, 2007;Chen et al, 2009;Lo et al, 2010;Mwinyi et al, 2010;Koh et al, 2012); however, the effects of estradiol on expression of other P450s remain unknown. In contrast, progesterone has been shown to enhance activities of pregnane X receptor (PXR)-driven promoters in various immortalized cell lines (Lehmann et al, 1998;Masuyama et al, 2003;Jeong et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Isoform-Specific Regulation of Cytochromes P450 Expression by Estradiol and Progesterone

Choi

Koh

Jeong

2013

Drug Metabolism and Disposition

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128

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“…To our knowledge, data regarding the regulation of the human ortholog CYP2B6 during pregnancy are still lacking. However, two recent articles found that high concentrations of estradiol induce 2B6 expression and activity in hepatocytes (Dickmann et al, 2008;Koh et al, 2012). Given this finding and the fact that estradiol levels are highest in mice at 18 to 19 days of gestation (McCormack and Greenwald, 1974), this may provide a plausible mechanism for the increased 2b10 expression observed at PD1.…”

Section: Discussionmentioning

confidence: 99%

Alteration of the Expression of Pesticide-Metabolizing Enzymes in Pregnant Mice: Potential Role in the Increased Vulnerability of the Developing Brain

Fortin

Aleksunes²,

Richardson

2013

Drug Metabolism and Disposition

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Studies on therapeutic drug disposition in humans have shown significant alterations as the result of pregnancy. However, it is not known whether pesticide metabolic capacity changes throughout pregnancy, which could affect exposure of the developing brain. We sought to determine the effect of pregnancy on the expression of hepatic enzymes involved in the metabolism of pesticides. Livers were collected from virgin and pregnant C57BL/6 mice at gestational days (GD)7, GD11, GD14, GD17, and postpartum days (PD)1, PD15, and PD30. Relative mRNA expression of several enzymes involved in the metabolism of pesticides, including hepatic cytochromes (Cyp) P450s, carboxylesterases (Ces), and paraoxonase 1 (Pon1), were assessed in mice during gestation and the postpartum period. Compared with virgin mice, alterations in the expression occurred at multiple time points, with the largest changes observed on GD14. At this time point, the expression of most of the Cyps involved in pesticide metabolism in the liver (Cyp1a2, Cyp2d22, Cyp2c37, Cyp2c50, Cyp2c54, and Cyp3a11) were downregulated by 30% or more. Expression of various Ces isoforms and Pon1 were also decreased along with Pon1 activity. These data demonstrate significant alterations in the expression of key enzymes that detoxify pesticides during pregnancy, which could alter exposure of developing animals to these chemicals. IntroductionPesticides are widely used to protect crops, cattle, gardens, and households from infestations. In 2007, it was estimated that 93 million pounds of active ingredients were used in the United States, with organophosphate (OP), carbamate, and pyrethroid (PYR) insecticides the most commonly used (US EPA 2011). Although pesticides are an important tool for ensuring an adequate food supply and protecting public health, there is a risk of untoward effects in nontarget species, including humans, because target and nontarget species often possess a common molecular target of the pesticide. Of particular concern with insecticides, such as OPs and PYRs, is their targeting of the nervous system and the potential increased vulnerability of the developing brain to their neurotoxic effects (Shafer et al., 2005;Jurewicz and Hanke, 2008).Several animal studies have consistently demonstrated that very young animals are more sensitive to the acute toxic effects of OPs and PYRs and that this increased sensitivity is likely the result of immature (Eskenazi et al., 2007), and more than 80% had detectable levels of the OP metabolite dimethylthiophosphate (Woodruff et al., 2011). Similarly, data from the 1999-2002 National Health and Nutrition Examination Survey found that 67% of pregnant women had detectable levels of the PYR metabolite 3-phenoxybenzoic acid (Castorina et al., 2010). Thus, there is widespread exposure of pregnant women to OP and PYR pesticides.Human pregnancy is known to cause a number of physiologic changes that may alter the metabolism of drugs and toxicants, including changes that increase absorption and decrease plasma protein leve...

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Estradiol induces cytochrome P450 2B6 expression at high concentrations: Implication in estrogen-mediated gene regulation in pregnancy

Cited by 54 publications

References 42 publications

Induction of Hepatic CYP3A Enzymes by Pregnancy-Related Hormones: Studies in Human Hepatocytes and Hepatic Cell Lines

Induction of Hepatic CYP3A Enzymes by Pregnancy-Related Hormones: Studies in Human Hepatocytes and Hepatic Cell Lines

Isoform-Specific Regulation of Cytochromes P450 Expression by Estradiol and Progesterone

Alteration of the Expression of Pesticide-Metabolizing Enzymes in Pregnant Mice: Potential Role in the Increased Vulnerability of the Developing Brain

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