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首页> 外文期刊>Biochemical Pharmacology >Reactive oxygen species generation and its role in the differential cytotoxicity of the arylhydroxylamine metabolites of sulfamethoxazole and dapsone in normal human epidermal keratinocytes.
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Reactive oxygen species generation and its role in the differential cytotoxicity of the arylhydroxylamine metabolites of sulfamethoxazole and dapsone in normal human epidermal keratinocytes.

机译：正常人表皮角质形成细胞中活性氧的产生及其在磺胺甲基异恶唑和氨苯砜的芳基羟胺代谢产物的差异细胞毒性中的作用。

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摘要

Cutaneous drug reactions (CDR) are responsible for numerous minor to life-threatening complications. Though the exact mechanism for CDR is not completely understood, evidence suggests that bioactivation of drugs to reactive oxygen or nitrogen species is an important factor in the initiation of these reactions. Several CDR-inducing drugs having an arylamine functional group, such as sulfamethoxazole (SMX) and dapsone (DDS), undergo bioactivation to reactive arylhydroxylamine metabolites. These metabolites can generate cellular oxidative stress by forming reactive oxygen species (ROS). Several studies have demonstrated a higher cytotoxicity with DDS hydroxylamine (DDS-NOH) compared to SMX hydroxylamine (SMX-NOH). To investigate the role of differential ROS generation in the higher cytotoxicity of DDS-NOH, hydroxylamine metabolites of SMX and DDS were synthesized and ROS formation by these metabolites determined. DDS-NOH and its analogues/metabolites consistently resulted in higher ROS formation as compared to SMX-NOH. However, comparison of the ROS generation and cytotoxicity of a series of arylhydroxylamine analogues of DDS did not support a simple correlation between ROS generation and cell death. Numerous ROS scavengers were found to reduce metabolite-induced ROS formation, with differences in the potency between the agents. The decrease in DDS-NOH-induced ROS generation in NHEK with ascorbic acid, N-acetylcysteine, Trolox, and melatonin was 87, 86, 44, and 16%, respectively. Similarly, the cytotoxicity and adduct formation of DDS-NOH in NHEK was reduced in the presence of ascorbic acid. In summary, these studies show that arylhydroxylamine metabolites of SMX/DDS induce ROS generation in NHEK, though such generation is not directly related to cytotoxicity.
机译：皮肤药物反应（CDR）导致许多次要的威胁生命的并发症。尽管尚未完全了解CDR的确切机制，但证据表明药物对活性氧或氮物种的生物激活是引发这些反应的重要因素。几种具有芳基胺官能团的CDR诱导药物，如磺胺甲基异恶唑（SMX）和氨苯砜（DDS），都经过生物活化作用生成反应性芳基羟胺代谢物。这些代谢物可通过形成活性氧（ROS）来产生细胞氧化应激。几项研究表明，与SMX羟胺（SMX-NOH）相比，DDS羟胺（DDS-NOH）具有更高的细胞毒性。为了研究不同的ROS产生在DDS-NOH更高细胞毒性中的作用，合成了SMX和DDS的羟胺代谢物，并确定了这些代谢物的ROS形成。与SMX-NOH相比，DDS-NOH及其类似物/代谢物始终导致更高的ROS形成。但是，比较ROS生成和一系列DDS芳基羟胺类似物的细胞毒性并不支持ROS生成与细胞死亡之间的简单关联。发现许多ROS清除剂可减少代谢物诱导的ROS形成，且各药之间的效力不同。抗坏血酸，N-乙酰半胱氨酸，Trolox和褪黑激素在NHEK中DDS-NOH诱导的ROS产生的减少分别为87％，86％，44％和16％。同样，在抗坏血酸的存在下，NHDS中DDS-NOH的细胞毒性和加合物形成减少。总之，这些研究表明，SMX / DDS的芳基羟胺代谢物在NHEK中诱导ROS生成，尽管这种生成与细胞毒性没有直接关系。

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