Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, PR China.
Comp Biochem Physiol C Toxicol Pharmacol. 2009 Jul;150(1):57-64. doi: 10.1016/j.cbpc.2009.02.008. Epub 2009 Mar 1.
Cytochrome P450s play an important role in the biotransformation of endogenous substrates and xenobiotics; however, little is known about the function of the CYP4T subfamily in the transformation of environmental pollutants in fish. We isolated a full-length cDNA sequence (designated as CYP4T11) from rare minnow (Gobiocypris rarus) liver by rapid amplification of cDNA ends. The open reading frame encoded a 467-residue protein that exhibited 87% and 71% identity with zebrafish CYP4T8 and European sea bass CYP4T2, respectively. CYP4T11 was predominantly expressed in liver and intestine with lower expression in the gill and brain. To further examine the function of CYP4T11 in pollutant metabolism, the effects of perfluorooctanoic acid (PFOA) exposure on the transcriptional expression of CYP4T11 and two possible upstream regulators, peroxisome proliferator-activated receptor alpha (PPARalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma), were determined in rare minnow gills and livers. PFOA induced a consistent significant upregulation of both PPARalpha and PPARgamma and a nonsignificant increase of CYP4T11 in the gill. In the liver, induced expression of PPARgamma was observed, although no obvious changes in PPARalpha expression were observed. Induction of CYP4T11 was only observed in males at the highest concentration of PFOA. These results suggest that the PPAR-CYP4T11 signaling pathway may be involved in PFOA-induced gill toxicity. Since the induced expression of CYP4T11 in liver was not consistent with the PPAR regulators, complex tissue-specific transcriptional regulation of CYP4T11 following PFOA exposure likely occurs.
细胞色素 P450s 在生物转化内源性底物和外源性化学物质中起着重要作用；然而，对于 CYP4T 亚家族在鱼类环境污染物转化中的功能知之甚少。我们通过快速扩增 cDNA 末端从稀有鮈鲫（Gobiocypris rarus）肝脏中分离出全长 cDNA 序列（命名为 CYP4T11）。开放阅读框编码一个 467 个残基的蛋白质，与斑马鱼 CYP4T8 和欧洲鲈鱼 CYP4T2 分别具有 87%和 71%的同一性。CYP4T11 在肝脏和肠道中表达为主，在鳃和脑中表达较低。为了进一步研究 CYP4T11 在污染物代谢中的功能，在稀有鮈鲫鳃和肝脏中测定了全氟辛酸（PFOA）暴露对 CYP4T11 及其两个可能的上游调节因子过氧化物酶体增殖物激活受体α（PPARα）和过氧化物酶体增殖物激活受体γ（PPARγ）转录表达的影响。PFOA 一致诱导了 PPARα 和 PPARγ 的显著上调，而在鳃中 CYP4T11 的上调不明显。在肝脏中观察到 PPARγ 的诱导表达，尽管 PPARα 的表达没有明显变化。仅在雄性鱼的最高 PFOA 浓度下观察到 CYP4T11 的诱导表达。这些结果表明，PPAR-CYP4T11 信号通路可能参与了 PFOA 诱导的鳃毒性。由于 CYP4T11 在肝脏中的诱导表达与 PPAR 调节剂不一致，因此 PFOA 暴露后 CYP4T11 的复杂组织特异性转录调节可能发生。
