Structural basis of species differences between human and experimental animal CYP1A1s in metabolism of 3,3',4,4',5-pentachlorobiphenyl.
Structural basis of species differences between human and experimental animal CYP1A1s in metabolism of 3,3',4,4',5-pentachlorobiphenyl.
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DOI：
10.1093/jb/mvr009
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发表时间：
2011-04
影响因子：
2.7
通讯作者：
K. Yamazaki;Motoharu Suzuki;T. Itoh;Keiko Yamamoto;Miki Kanemitsu;C. Matsumura;T. Nakano;T. Sakaki;Y. Fukami;H. Imaishi;Hideyuki Inui
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文献类型：
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作者：
K. Yamazaki;Motoharu Suzuki;T. Itoh;Keiko Yamamoto;Miki Kanemitsu;C. Matsumura;T. Nakano;T. Sakaki;Y. Fukami;H. Imaishi;Hideyuki Inui
二恶英类化合物中含有的共面多氯联苯会在生物体内积累，对野生动物和人类健康造成不利影响。尽管许多研究人员已经对多氯联苯的代谢进行了研究，但3，3‘，4，4’，5-五氯联苯(PCB126)的体外代谢研究很少，尽管它是多氯联苯同系物中毒性最高的。细胞色素P450(CYP)1A1蛋白可以羟化代谢部分二恶英和多氯联苯，但人和大鼠细胞色素P450 1A1蛋白的活性有很大差异。其机制尚不清楚。从我们的结果来看，大鼠的细胞色素P41A1代谢PCB126为4-羟基-3，3‘，4’，5-四氯联苯和4-羟基-3，3‘，4’，5，5‘-五氯联苯，而人的细胞色素P1A1不代谢。两种CYP蛋白质的同源模型和对接研究表明，形成它们与底物结合的腔的氨基酸残基的不同导致了腔的大小和形状的不同；只有大鼠CYP1A1的腔允许PCB126与血红素足够近的地方进行代谢。比较其他哺乳动物CYP1A1蛋白的氨基酸残基表明，大鼠对外源物质具有独特的代谢。我们的结果表明，在对以大鼠为实验动物估计的毒性数据进行人类外推时，特别是在由CYP1A1代谢的化合物的情况下，有必要谨慎。
Coplanar polychlorinated biphenyls included in dioxin-like compounds are bio-accumulated and adversely affect wildlife and human health. Although many researchers have studied the metabolism of PCBs, there have been few reports of the in vitro metabolism of 3,3',4,4',5-pentachlorobiphenyl (PCB126), despite the fact that it has the highest toxicity among PCB congeners. Cytochrome P450 (CYP) 1A1 proteins can metabolize some dioxins and PCBs by hydroxylation, but the activities of human and rat CYP1A1 proteins are very different. The mechanism remains unclear. From our results, rat CYP1A1 metabolized PCB126 into 4-OH-3,3',4',5-tetrachlorobiphenyl and 4-OH-3,3',4',5,5'-pentachlorobiphenyl, but human CYP1A1 did not metabolize. Homology models of the two CYP proteins, and docking studies, showed that differences in the amino acid residues forming their substrate-binding cavities led to differences in the size and shape of the cavities; only the cavity of rat CYP1A1 allowed PCB126 close enough to the haem to be metabolized. Comparison of the amino acid residues of other mammalian CYP1A1 proteins suggested that rats have a unique metabolism of xenobiotics. Our results suggest that it is necessary to be careful in human extrapolation of toxicity data estimated by using the rat as an experimental animal, especially in the case of compounds metabolized by CYP1A1.