Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany.
Institute of Clinical Pharmacology, University Hospital of RWTH, 52074, Aachen, Germany.
Arch Toxicol. 2024 Nov;98(11):3739-3753. doi: 10.1007/s00204-024-03836-w. Epub 2024 Aug 13.
Despite extensive research on the metabolism of polychlorinated biphenyls (PCBs), knowledge gaps persist regarding their isoform-specific biotransformation pathways. This study aimed to elucidate the role of different cytochrome P450 enzymes in PCB metabolism, focusing on WHO-congeners 2,4,4'-trichlorobiphenyl (PCB28), 2,2',5,5'-tetrachlorobiphenyl (PCB52), and 2,2',4,5,5'-pentachlorobiphenyl (PCB101). Utilizing engineered HEK293 cell lines, we investigated the in vitro metabolism of these PCBs by CYP1A2, CYP2C8, CYP2C9, CYP3A4, CYP2A6, and CYP2E1, revealing robust production of hydroxylated metabolites. Our results show that CYP2A6 plays a major role in the metabolism of these congeners responsible for predominant formation of para-position hydroxylated metabolites, with concentrations reaching up to 1.61 µg/L (5,89 nM) for PCB28, 316.98 µg/L (1,03 µM) for PCB52, and 151.1 µg/L (441 nM) for PCB101 from a 20 µM parent PCB concentration. Moreover, concentration-dependent cytotoxic and cytostatic effects induced by reactive intermediates of the PCB hydroxylation pathway were observed in HEK293CYP2A6 cells, for all three congeners tested. CYP2A6 was specifically capable of activating PCBs 28 and 101 to genotoxic metabolites which produced genetic defects which were propagated to subsequent generations, potentially contributing to carcinogenesis. In a clinical study examining CYP2A6 enzyme activity in formerly exposed individuals with elevated internal PCB levels, a participant with increased enzyme activity showed a direct association between the phenotypic activity of CYP2A6 and the metabolism of PCB28, confirming the role of CYP2A6 in the in vivo metabolism of PCB28 also in humans. These results altogether reinforce the concept that CYP2A6 plays a pivotal role in PCB congener metabolism and suggest its significance in human health, particularly in the metabolism of lower chlorinated, volatile PCB congeners.
尽管对多氯联苯（PCBs）的代谢进行了广泛的研究，但对于其同型特异性生物转化途径仍存在知识空白。本研究旨在阐明不同细胞色素 P450 酶在 PCB 代谢中的作用，重点研究世界卫生组织相关的 2,4,4'-三氯联苯（PCB28）、2,2',5,5'-四氯联苯（PCB52）和 2,2',4,5,5'-五氯联苯（PCB101）。利用工程化的 HEK293 细胞系，我们研究了这些 PCB 被 CYP1A2、CYP2C8、CYP2C9、CYP3A4、CYP2A6 和 CYP2E1 体外代谢的情况，发现它们能够生成大量的羟基化代谢产物。研究结果表明，CYP2A6 在这些同型物的代谢中起着重要作用，主要负责形成对位羟基化代谢产物，其浓度可达 20µM 母体 PCB 浓度下 PCB28 的 1.61µg/L（5,89nM）、PCB52 的 316.98µg/L（1,03µM）和 PCB101 的 151.1µg/L（441nM）。此外，在所有三种测试同型物中，均观察到 PCB 羟基化途径的反应中间体引起的 HEK293CYP2A6 细胞的浓度依赖性细胞毒性和细胞增殖抑制作用。CYP2A6 能够将 PCB28 和 PCB101 激活为遗传毒性代谢产物，这些代谢产物会导致遗传缺陷，并传播到后代，可能导致致癌作用。在一项对体内 PCB 水平升高的曾暴露个体中 CYP2A6 酶活性的临床研究中，具有较高酶活性的参与者显示出 CYP2A6 表型活性与 PCB28 代谢之间存在直接关联，这证实了 CYP2A6 在人体中也参与了 PCB28 的体内代谢。这些结果共同强化了 CYP2A6 在 PCB 同型物代谢中发挥关键作用的概念，并提示其在人类健康中的重要性，特别是在代谢低氯代、挥发性 PCB 同型物方面。
