BackgroundInfections classified as group 1 biological carcinogens include the helminthiases caused by Schistosoma haematobium and Opisthorchis viverrini. The molecular mediators underlying the infection with these parasites and cancer remain unclear. Although carcinogenesis is a multistep process, we have postulated that these parasites release metabolites including oxysterols and estrogen-like metabolites that interact with host cell DNA. How and why the parasite produce/excrete these metabolites remain unclear. A gene encoding a CYP enzyme was identified in schistosomes and opisthorchiids. Therefore, it is reasonable hypothesized that CYP 450 might play a role in generation of pro-inflammatory and potentially carcinogenic compounds produced by helminth parasites such as oxysterols and catechol estrogens. Here, we performed enzymatic assays using several isoforms of CYP 450 as CYP1A1, 2E1 and 3A4 which are involved in the metabolism of chemical carcinogens that have been associated with several cancer. The main aim was the analysis of the role of these enzymes in production of helminth-associated metabolites and DNA-adducts.MethodThe effect of cytochrome P450 enzymes CYP 1A1, 2E1 and 3A4 during the interaction between DNA, glycocholic acid and taurochenodeoxycholate sodium on the formation of DNA-adducts and metabolites associated with urogenital schistosomiasis (UGS) and opisthorchiasis was investigated in vitro. Liquid chromatography/mass spectrometry was used to detect and identify metabolites.Main findingsThrough the enzymatic assays we provide a deeper understanding of how metabolites derived from helminths are formed and the influence of CYP 450. The assays using compounds similar to those previously observed in helminths as glycocholic acid and taurochenodeoxycholate sodium, allowed the detection of metabolites in their oxidized form and their with DNA. Remarkably, these metabolites were previously associated with schistosomiaisis and opisthorchiasis. Thus, in the future, it may be possible to synthesize this type of metabolites through this methodology and use them in cell lines to clarify the carcinogenesis process associated with these diseases.Principal conclusionsMetabolites similar to those detected in helminths are able to interact with DNA in vitro leading to the formation of DNA adducts. These evidences supported the previous postulate that imply helminth-like metabolites as initiators of helminthiases-associated carcinogenesis. Nonetheless, studies including these kinds of metabolites and cell lines in order to evaluate its potential carcinogenic are required.

中文翻译：

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致癌蠕虫寄生虫的感染及其代谢物的产生会诱导 DNA 加合物的形成

背景分类为第 1 组生物致癌物的感染包括由血吸虫和 Opisthorchis viverrini 引起的蠕虫病。感染这些寄生虫和癌症的分子介质仍不清楚。虽然致癌是一个多步骤的过程，但我们假设这些寄生虫释放代谢物，包括与宿主细胞 DNA 相互作用的氧甾醇和雌激素样代谢物。寄生虫如何以及为何产生/排泄这些代谢物仍不清楚。在血吸虫和 opisthorchiids 中发现了一个编码 CYP 酶的基因。因此，有理由假设 CYP 450 可能在蠕虫寄生虫（如氧甾醇和儿茶酚雌激素）产生的促炎和潜在致癌化合物中发挥作用。这里，我们使用 CYP 450 的几种同工型作为 CYP1A1、2E1 和 3A4 进行了酶促测定，这些同工型参与了与几种癌症相关的化学致癌物的代谢。主要目的是分析这些酶在产生蠕虫相关代谢物和 DNA 加合物中的作用。在体外研究了与泌尿生殖道血吸虫病 (UGS) 和弓形虫病相关的 DNA 加合物和代谢物。液相色谱/质谱用于检测和鉴定代谢物 主要发现 通过酶分析，我们更深入地了解了蠕虫代谢物是如何形成的以及 CYP 450 的影响。使用与先前在蠕虫中观察到的化合物相似的化合物（如甘胆酸和牛磺鹅去氧胆酸钠）进行的测定允许检测其氧化形式和 DNA 的代谢物。值得注意的是，这些代谢物以前与血吸虫病和后睾吸虫病有关。因此，在未来，有可能通过这种方法合成这种类型的代谢物，并在细胞系中使用它们来阐明与这些疾病相关的致癌过程。体外导致 DNA 加合物的形成。这些证据支持先前的假设，即蠕虫样代谢物是蠕虫酶相关致癌作用的引发剂。尽管如此，