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

Choi, Sang Hyoun; Koh, Kyung Bong; Jeong, Hyunyoung

doi:10.1124/dmd.112.046276

Cited by 121 publications

(109 citation statements)

References 46 publications

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“…However, this does not signify that estradiol or progesterone (or both) induces CYP3A activity at plasma concentrations observed in pregnant women. Indeed, consistent with our data, at these lower plasma concentrations of estradiol or progesterone, these hormones failed to consistently induce CYP3A activity in human hepatocytes (Choi et al, 2013).…”

Section: Discussionsupporting

confidence: 91%

Prediction of Gestational Age–Dependent Induction of In Vivo Hepatic CYP3A Activity Based on HepaRG Cells and Human Hepatocytes

et al. 2015

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In pregnant women, CYP3A activity increases by 100% during the third trimester (T3). Due to logistical and ethical constraints, little is known about the magnitude of CYP3A induction during the first trimester (T1) and second trimester (T2). Our laboratory has shown that sandwichcultured human hepatocytes (SCHH) and HepaRG cells have the potential to predict the magnitude of in vivo induction of CYP3A activity likely to be observed in T1 and T2. Therefore, we incubated SCHH and HepaRG cells with plasma concentrations of various pregnancyrelated hormones (PRHs)-individually or in combination-observed during T1, T2, or T3 in pregnant women. Then, CYP3A activity was measured by 19-OH-midazolam formation. In all three trimesters, only cortisol (C) consistently and significantly induced CYP3A activity, while other individual hormones (progesterone, estradiol, or growth hormones) failed to induce CYP3A activity. At physiologically relevant 13 plasma concentrations, the magnitude of CYP3A induction by C or the combination of all PRHs did not change significantly with gestational age. The pattern of induction of CYP3A activity in SCHH by the hormones was similar to that in HepaRG cells. Based on these data, we conclude that C remains the major inducer of CYP3A activity earlier in gestation. Moreover, we predict that the magnitude of CYP3A induction during T1 and T2 will be similar to that observed during T3 (∼100% increase versus postpartum). This prediction is consistent with the observation of similar increases in T2 and T3 oral clearance of indinavir (a CYP3A cleared drug) versus postpartum.

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Section: Discussionsupporting

confidence: 91%

Prediction of Gestational Age–Dependent Induction of In Vivo Hepatic CYP3A Activity Based on HepaRG Cells and Human Hepatocytes

et al. 2015

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“…Progesterone was a less potent inducer than cortisol, because it was able to generate a statistically significant effect on CYP3A activity and CYP3A4 transcripts in only a few cases. 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).…”

Section: Discussionsupporting

confidence: 46%

“…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: 53%

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

2012

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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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“…Pregnancy is also accompanied by increases in plasma concentrations of multiple hormones including estrogen, progesterone, and corticosteroids, and these hormones may be in part responsible for altered drug metabolism during pregnancy. For example, results from previous studies indicate that rising concentrations of estrogen and progesterone may lead to increased elimination of CYP2B6 and CYP3A4 substrate drugs during pregnancy (Koh et al, 2012;Choi et al, 2013;Papageorgiou et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Human Placental Lactogen Induces CYP2E1 Expression via PI 3-Kinase Pathway in Female Human Hepatocytes

et al. 2014

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The state of pregnancy is known to alter hepatic drug metabolism. Hormones that rise during pregnancy are potentially responsible for the changes. Here we report the effects of prolactin (PRL), placental lactogen (PL), and growth hormone variant (GH-v) on expression of major hepatic cytochromes P450 expression and a potential molecular mechanism underlying CYP2E1 induction by PL. In female human hepatocytes, PRL and GH-v showed either no effect or small and variable effects on mRNA expression of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5. On the other hand, PL increased expression level of CYP2E1 mRNA with corresponding increases in CYP2E1 protein and activity levels. Results from hepatocytes and HepaRG cells indicate that PL does not affect the expression or activity of HNF1a, the known transcriptional activator of basal CYP2E1 expression. Furthermore, transient transfection studies and Western blot results showed that STAT signaling, the previously known mediator of PL actions in certain tissues, does not play a role in CYP2E1 induction by PL. A chemical inhibitor of PI3-kinase signaling significantly repressed the CYP2E1 induction by PL in human hepatocytes, suggesting involvement of PI3-kinase pathway in CYP2E1 regulation by PL. CYP2E1-humanized mice did not exhibit enhanced CYP2E1 expression during pregnancy, potentially because of interspecies differences in PL physiology. Taken together, these results indicate that PL induces CYP2E1 expression via PI3-kinase pathway in human hepatocytes.

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

Cited by 121 publications

References 46 publications

Prediction of Gestational Age–Dependent Induction of In Vivo Hepatic CYP3A Activity Based on HepaRG Cells and Human Hepatocytes

Prediction of Gestational Age–Dependent Induction of In Vivo Hepatic CYP3A Activity Based on HepaRG Cells and Human Hepatocytes

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

Human Placental Lactogen Induces CYP2E1 Expression via PI 3-Kinase Pathway in Female Human Hepatocytes

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