Nitogen reduction and xenobiotic response

项目摘要：羟胺和亚硝基代谢物与肺炎的发病机制有关 磺胺甲恶唑(SMX)和其他芳胺类药物的不良反应。自发性羟胺 氧化为活性亚硝基代谢物，在SMX的情况下，可以触发迟发性超敏反应 反应。这些过敏反应干扰了SMX的有效使用，SMX是 预防免疫功能低下患者机会性感染的选择。新陈代谢研究 SMX过敏的危险因素在很大程度上产生了负面结果；然而，这些研究并没有 考虑了羟胺和亚硝基代谢物的还原代谢。我们最近展示了 羟胺被黄素蛋白NADH细胞色素b5还原酶(B5R)和 血红蛋白细胞色素b5(Cyt B5)，通过一种新的、直接的异种生物还原途径。我们还有 研究表明，除硫醇外，抗坏血酸还提供亚硝基还原的主要途径。我们的整体 假说是羟胺或亚硝基还原受损使患者容易出现不良反应 芳胺类化合物，如对SMX过敏。我们将首先讨论这一假设 B5R基因中羟胺还原的变异性及其与遗传多态的关系 人类的细胞色素b5基因。我们接下来将确定羟胺或亚硝基还原的变化是否会影响 抗坏血酸、硫醇或黄素限制对SMX代谢物的免疫原性反应 模特。最后，我们将确定羟胺或亚硝基还原受损是否为 SMX超敏反应，在一项免疫功能低下的淋巴系统恶性肿瘤患者的前瞻性研究中。 这些研究将促进我们对SMX过敏机制的理解，并将 表征异种生物减少的新的直接途径的个体变异性，具有临床意义 对许多化合物的反应，包括胺肟类前体药物和芳胺类致癌物质，此外 致SMX。 相关性：这些研究将帮助我们更好地理解导致“磺胺类药物”的个体风险因素。 通过了解不同药物代谢磺胺类药物的不同方式，在人们中产生过敏反应 人民。这些研究的最终目标是找到更好的方法来预防这些不良反应。

Project summary: Hydroxylamine and nitroso metabolites have been implicated in the pathogenesis of adverse reactions to sulfamethoxazole (SMX) and other arylamine drugs. Hydroxylamines spontaneously oxidize to reactive nitroso metabolites, which, in the case of SMX, can trigger delayed-type hypersensitivity reactions. These hypersensitivity reactions interfere with the effective use of SMX, which is the drug of choice for the prevention of opportunistic infections in immunocompromised patients. Studies of metabolic risk factors for SMX hypersensitivity have largely yielded negative results; however, these studies have not considered the reductive metabolism of hydroxylamine and nitroso metabolites. We have recently shown that hydroxylamines are detoxified by the flavoprotein NADH cytochrome b5 reductase (b5R) and the hemeprotein cytochrome b5 (cyt b5), through a novel, direct pathway of xenobiotic reduction. We have also shown that ascorbate, in addition to thiols, provides a major pathway of nitroso reduction. Our overall hypothesis is that impaired hydroxylamine or nitroso reduction predisposes patients to adverse reactions to arylamine compounds, such as hypersensitivity to SMX. We will address this hypothesis by first characterizing variability in hydroxylamine reduction and its relationship to genetic polymorphisms in b5R or cyt b5 in humans. We will next determine whether alterations in hydroxylamine or nitroso reduction influence the immunogenic response to SMX metabolites, using ascorbate, thiol, or flavin restriction in a guinea pig model. Finally, we will determine whether impaired hydroxylamine or nitroso reduction is a risk factor for SMX hypersensitivity, in a prospective study of immunocompromised patients with lymphoid malignancies. These studies will advance our understanding of the mechanisms underlying SMX hypersensitivity, and will characterize individual variability in a novel direct pathway of xenobiotic reduction, with clinical implications for responses to many compounds, including amidoxime pro-drugs and arylamine carcinogens, in addition to SMX. Relevance: These studies will help us to better understand individual risk factors that lead to "sulfa drug" allergies in people, by learning about differences in the ways that sulfa drugs are metabolized by different people. The ultimate goal of these studies is to find better ways to prevent these adverse reactions.