尽管对多氯联苯(PCBs)的代谢进行了广泛的研究,关于其同工型特异性生物转化途径的知识差距仍然存在。本研究旨在阐明不同细胞色素P450酶在PCB代谢中的作用。重点关注WHO同源物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HEK293细胞系,我们研究了CYP1A2,CYP2C8,CYP2C9,CYP3A4,CYP2A6和CYP2E1对这些多氯联苯的体外代谢,揭示了羟基化代谢产物的强劲产生。我们的结果表明,CYP2A6在这些同源物的代谢中起主要作用,这些同源物负责对位羟基化代谢物的主要形成,从20µM母体PCB浓度,PCB28的浓度达到1.61µg/L(5,89nM),PCB52的浓度达到316.98µg/L(1,03µM),PCB101的浓度达到151.1µg/L(441nM)。此外,在HEK293CYP2A6细胞中观察到PCB羟基化途径的反应性中间体诱导的浓度依赖性细胞毒性和细胞抑制作用,对所有三个同源物进行了测试。CYP2A6特别能够将多氯联苯28和101激活为基因毒性代谢物,这些代谢物产生遗传缺陷,并传播到后代。潜在的致癌作用.在一项临床研究中,检查了先前暴露于体内PCB水平升高的个体的CYP2A6酶活性,酶活性增加的参与者显示CYP2A6的表型活性与PCB28的代谢之间存在直接关联,证实了CYP2A6在人类体内PCB28代谢中的作用.这些结果完全强化了CYP2A6在PCB同源物代谢中起关键作用的概念,并表明其在人类健康中的意义。特别是在低氯化的代谢中,挥发性PCB同源物。
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.