The molecular toxicology of the chemical warfare agent sulfur mustard (SM) is still not completely understood. It has been suggested that in addition to SM itself also biotransformation products thereof mediate cytotoxicity. In the current study, we assessed this aspect by exposing a human hepatocyte cell line (HepG2) to SM or to its oxidation products sulfur mustard sulfoxide (SMO), sulfur mustard sulfone (SMO2), and divinyl sulfone (DVS). Cytotoxicity, determined with the XTT assay, revealed a significant higher toxicity of SMO2 and DVS compared to SM while SMO had no effect at any concentration. The exact biotransformation of SM leading to SMO, SMO2 and finally DVS is unknown so far. Involvement of the CYP450 system is discussed and was also investigated in the presented study. Modulation of CYP1A2 activity, taken as a model enzyme for CYP450, affected cytotoxicity of SM, SMO2 or DVS significantly. Induction of CYP1A2 with omeprazole led to decreased cytotoxicity for all compounds whereas inhibition with cimetidine resulted in an increased cytotoxicity for SM, but not for SMO2 and DVS. Our results indicate a distinctive role of the CYP450 system in SM poisoning. Future studies should address the metabolic conversion of SM in more detail. Our data may suggest the well-tolerated drug omeprazole as a potential co-treatment after contact to SM.

中文翻译：

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硫芥及其氧化产物的体外毒性比较

化学战剂硫芥 (SM) 的分子毒理学仍未完全了解。已经提出，除了SM本身之外，其生物转化产物也介导细胞毒性。在当前的研究中，我们通过将人类肝细胞系 (HepG2) 暴露于 SM 或其氧化产物硫芥亚砜 (SMO)、硫芥子砜 (SMO2) 和二乙烯基砜 (DVS) 来评估这一方面。用 XTT 测定确定的细胞毒性显示，与 SM 相比，SMO2 和 DVS 的毒性显着更高，而 SMO 在任何浓度下都没有影响。到目前为止，SM 导致 SMO、SMO2 和最终 DVS 的确切生物转化尚不清楚。讨论了 CYP450 系统的参与，并在本研究中进行了调查。CYP1A2 活性的调节，作为 CYP450 的模型酶，SM、SMO2 或 DVS 的细胞毒性显着影响。用奥美拉唑诱导 CYP1A2 导致所有化合物的细胞毒性降低，而西咪替丁的抑制导致 SM 的细胞毒性增加，但对 SMO2 和 DVS 没有。我们的结果表明 CYP450 系统在 SM 中毒中的独特作用。未来的研究应该更详细地解决 SM 的代谢转化。我们的数据可能表明耐受性良好的药物奥美拉唑可作为与 SM 接触后的潜在联合治疗。未来的研究应该更详细地解决 SM 的代谢转化。我们的数据可能表明耐受性良好的药物奥美拉唑可作为与 SM 接触后的潜在联合治疗。未来的研究应该更详细地解决 SM 的代谢转化。我们的数据可能表明耐受性良好的药物奥美拉唑可作为与 SM 接触后的潜在联合治疗。