Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers
Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers
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DOI：
10.1124/jpet.106.112136
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Wang, Hongbing
中科院分区：
文献类型：
--
作者：
Faucette, Stephanie R.;Zhang, Tong-Cun;Wang, Hongbing
人雄烷X受体（hPXR）和组成型雄烷受体（hCAR）都能够调节CYP 3A 4和CYP 2B 6基因表达。然而，目前鉴定的大多数CYP 3A 4和CYP 2B 6诱导剂是经证实的hPXR激活剂，而不是hCAR激活剂。为了比较这些受体的化学选择性，评价了已知诱导CYP 3A 4和/或CYP 2B表达的16种药物对hPXR相对于hCAR的相对活化。由于永生化细胞中hCAR的高基础但低化学诱导的活化，使用替代方法来评估hCAR活化潜力。16种化合物中有13种被归类为中度至强hPXR激活剂。相比之下，卡马西平（CMZ）、依法韦仑（EFV）和奈韦拉平（NVP）在与原代人肝细胞中有效CYP 2B 6报告基因或内源性基因诱导相关的浓度下被归类为可忽略或弱hPXR激活剂，表明hCAR的潜在激活作用。随后的实验表明，这三种药物有效地诱导体内转染的增强型黄色荧光蛋白-hCAR的核积聚，并且当在CAR（-/-）小鼠中表达hCAR时，显著增加CYP 2B 6报告基因的表达。此外，使用最近鉴定的hCAR的化学响应性剪接变体（hCAR 3），评价了16种化合物的hCAR活化谱。通过结合基于hPXR和hCAR 3的报告基因测定的结果，将这些诱导剂分类为hPXR、hCAR或hPXR/hCAR双重激活剂。我们的研究结果表明，CMZ，EFV和NVP诱导CYP 2B 6和CYP 3A 4优先通过hCAR和hCAR 3代表了体外预测化学介导的人CAR活化的敏感工具。
Both the human pregnane X receptor (hPXR) and constitutive androstane receptor (hCAR) are capable of regulating CYP3A4 and CYP2B6 gene expression. However, the majority of currently identified CYP3A4 and CYP2B6 inducers are confirmed activators of hPXR but not hCAR. To compare these receptors with respect to their chemical selectivities, 16 drugs known to induce CYP3A4 and/or CYP2B expression were evaluated for relative activation of hPXR versus hCAR. Because of the high basal but low chemical-induced activation of hCAR in immortalized cells, alternative methods were used to evaluate hCAR activation potential. Thirteen of the 16 compounds were classified as moderate to strong hPXR activators. In contrast, carbamazepine (CMZ), efavirenz (EFV), and nevirapine (NVP) were classified as negligible or weak hPXR activators at concentrations associated with efficacious CYP2B6 reporter or endogenous gene induction in primary human hepatocytes, suggesting potential activation of hCAR. Subsequent experiments demonstrated that these three drugs efficiently induced nuclear accumulation of in vivo-transfected enhanced yellow fluorescent protein-hCAR and significantly increased expression of a CYP2B6 reporter gene when hCAR was expressed in CAR(-/-) mice. In addition, using a recently identified, chemically responsive splice variant of hCAR (hCAR3), the hCAR activation profiles of the 16 compounds were evaluated. By combining results from the hPXR- and hCAR3-based reporter gene assays, these inducers were classified as hPXR, hCAR, or hPXR/hCAR dual activators. Our results demonstrate that CMZ, EFV, and NVP induce CYP2B6 and CYP3A4 preferentially through hCAR and that hCAR3 represents a sensitive tool for in vitro prediction of chemical-mediated human CAR activation.