Metabolic activation of WHO-congeners PCB28, 52, and 101 by human CYP2A6: evidence from in vitro and in vivo experiments

IF 4.8 2区 医学 Q1 TOXICOLOGY Archives of Toxicology Pub Date : 2024-08-13 DOI:10.1007/s00204-024-03836-w
Isabella Randerath, Thomas Schettgen, Julian Peter Müller, Jens Rengelshausen, Susanne Ziegler, Nathalia Quinete, Jens Bertram, Salah Laieb, Elke Schaeffeler, Andrea Kaifie, Katja S. Just, Aaron Voigt, Roman Tremmel, Matthias Schwab, Julia C. Stingl, Thomas Kraus, Patrick Ziegler
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Abstract

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.

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人类 CYP2A6 对世卫组织致癌物质 PCB28、52 和 101 的代谢活化:来自体外和体内实验的证据。
尽管对多氯联苯(PCBs)的新陈代谢进行了广泛的研究,但有关其同工酶特异性生物转化途径的知识仍然存在差距。本研究旨在阐明不同细胞色素 P450 酶在多氯联苯代谢中的作用,重点研究世界卫生组织的致癌物质 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)。我们利用改造过的 HEK293 细胞系,研究了 CYP1A2、CYP2C8、CYP2C9、CYP3A4、CYP2A6 和 CYP2E1 对这些多氯联苯的体外代谢,结果发现羟化代谢产物的生成量很大。我们的研究结果表明,CYP2A6 在这些同系物的代谢过程中发挥了重要作用,主要负责形成对位羟基化代谢物,在浓度为 20 µM 的母体多氯联苯中,PCB28 的羟基化代谢物浓度高达 1.61 µg/L (5,89 nM),PCB52 的羟基化代谢物浓度高达 316.98 µg/L (1,03 µM),PCB101 的羟基化代谢物浓度高达 151.1 µg/L (441 nM)。此外,在 HEK293CYP2A6 细胞中,对于所测试的所有三种同系物,都观察到了 PCB 羟基化途径的反应性中间产物诱导的浓度依赖性细胞毒性和细胞抑制作用。CYP2A6 特别能够将多氯联苯 28 和 101 活化为具有遗传毒性的代谢物,从而产生遗传缺陷,并传播给后代,可能导致致癌。在一项临床研究中,对体内多氯联苯水平升高、曾接触过多氯联苯的人的 CYP2A6 酶活性进行了检测,结果显示,一名酶活性升高的参与者的 CYP2A6 表型活性与多氯联苯 28 的新陈代谢有直接联系,这证实了 CYP2A6 在多氯联苯 28 的体内新陈代谢中的作用。这些结果共同强化了 CYP2A6 在多氯联苯同系物代谢中发挥关键作用的概念,并表明其对人类健康的重要意义,特别是在低氯化、挥发性多氯联苯同系物的代谢中。
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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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