Lange Anke, Corcoran Jenna, Miyagawa Shinichi, Iguchi Taisen, Winter Matthew J, Tyler Charles R
University of Exeter, Biosciences, College of Life & Environmental Sciences, Exeter EX4 4QD, United Kingdom.
Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Department of Basic Biology, School of Life Science, SOKENDAI (Graduate University for Advanced Studies), 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan.
Toxicol In Vitro. 2017 Jun;41:114-122. doi: 10.1016/j.tiv.2017.02.023. Epub 2017 Mar 1.
In mammals, the pregnane X receptor (PXR) is a transcription factor with a key role in regulating expression of several genes involved in drug biotransformation. PXR is present in fish and some genes known to be under its control can be up-regulated by mammalian PXR ligands. Despite this, direct involvement of PXR in drug biotransformation in fish has yet to be established. Here, the full length PXR sequence was cloned from carp (Cyprinus carpio) and used in a luciferase reporter assay to elucidate its role in xenobiotic metabolism in fish. A reporter assay for human PXR (hPXR) was also established to compare transactivation between human and carp (cPXR) isoforms. Rifampicin activated hPXR as expected, but not cPXR. Conversely, clotrimazole (CTZ) activated both isoforms and was more potent on cPXR, with an EC50 within the range of concentrations of CTZ measured in the aquatic environment. Responses to other azoles tested were similar between both isoforms. A range of pharmaceuticals tested either failed to activate, or were very weakly active, on the cPXR or hPXR. Overall, these results indicate that the cPXR may differ from the hPXR in its responses and/or sensitivity to induction by different environmental chemicals, with implications for risk assessment because of species differences.
在哺乳动物中，孕烷X受体（PXR）是一种转录因子，在调节多个参与药物生物转化的基因的表达中起关键作用。PXR存在于鱼类中，已知受其控制的一些基因可被哺乳动物PXR配体上调。尽管如此，PXR在鱼类药物生物转化中的直接作用尚未得到证实。在此，从鲤鱼（Cyprinus carpio）中克隆了全长PXR序列，并用于荧光素酶报告基因测定，以阐明其在鱼类异生物质代谢中的作用。还建立了人类PXR（hPXR）的报告基因测定，以比较人类和鲤鱼（cPXR）异构体之间的反式激活作用。利福平如预期那样激活了hPXR，但未激活cPXR。相反，克霉唑（CTZ）激活了两种异构体，且对cPXR的作用更强，其半数有效浓度（EC50）在水环境中测得的CTZ浓度范围内。两种异构体对其他测试唑类的反应相似。一系列测试的药物对cPXR或hPXR要么未能激活，要么活性非常弱。总体而言，这些结果表明，cPXR在对不同环境化学物质诱导的反应和/或敏感性方面可能与hPXR不同，由于物种差异，这对风险评估具有影响。
