Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195-7610, USA.
Drug Metab Dispos. 2013 Feb;41(2):281-90. doi: 10.1124/dmd.112.049015. Epub 2012 Dec 6.
CYP3A activity is induced by approximately 2-fold during the third trimester of human pregnancy. Placental growth hormone (PGH), estrogens (primarily 17β-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, 1× total) and the 10× 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.
CYP3A 活性在人类妊娠的第三个 trimester 期间大约增加 2 倍。胎盘生长激素（PGH）、雌激素（主要是 17β-雌二醇）、皮质醇和孕酮有调节 CYP3A 活性的潜力。因此，我们确定这些激素在妊娠期间升高的血浆浓度是否诱导肝 CYP3A 表达。我们用来自绝经前女性供体的 sandwich-cultured human hepatocytes（SCHH）（n=2）孵育生理（未结合，1×总）和 10×总第三个 trimester 激素血浆浓度（单独和组合），并确定它们对 CYP3A 活性和 CYP3A4、CYP3A5 及其各自的激素受体（生长激素受体、糖皮质激素受体和雌激素受体 alpha）的影响。在所有激素中，皮质醇是最有效的 CYP3A 活性和 CYP3A4、CYP3A5 mRNA 表达诱导剂。PGH/生长激素和皮质醇的组合诱导 CYP3A 活性和表达的作用明显大于皮质醇单独作用。当用 SCHH 中未结合或总血浆浓度孵育所有激素时，CYP3A 活性被诱导至与第三个 trimester 期间体内观察到的程度相当。这些激素对激素受体的 mRNA 表达只有适度的影响。在 SCHH 中观察到的诱导模式在 HepaRG 细胞中得到复制，但在 HuH7/HepG2 细胞中没有得到复制。SCHH 或 HepaRG 细胞可用于确定妊娠期间 CYP3A 诱导的机制基础，并预测在第一个和第二个 trimester 期间可能观察到的诱导幅度，此时进行体内 CYP3A 活性表型研究在操作上具有挑战性。
