Nitogen reduction and xenobiotic response

描述（由申请人提供）：羟胺和亚硝基代谢物与磺胺甲恶唑（SMX）和其他芳胺药物不良反应的发病机制有关。羟胺会自发氧化为活性亚硝基代谢物，在SMX的情况下，这会引发迟发型超敏反应。这些超敏反应干扰SMX的有效使用，SMX是预防免疫功能低下患者机会性感染的首选药物。SMX超敏反应的代谢风险因素研究在很大程度上产生了负面结果;然而，这些研究没有考虑羟胺和亚硝基代谢物的还原代谢。我们最近发现，羟胺解毒的黄素蛋白NADH细胞色素b5还原酶（b5 R）和血红素蛋白细胞色素b5（细胞色素b5），通过一种新的，直接的途径异生素还原。我们还表明，抗坏血酸，除了硫醇，提供了一个主要的亚硝基还原途径。我们的总体假设是，受损的羟胺或亚硝基还原易使患者对芳胺化合物产生不良反应，如对SMX超敏反应。我们将解决这一假设，首先在羟胺还原和它的关系，在人类b5 R或细胞色素b5的遗传多态性的特点的变化。接下来，我们将在豚鼠模型中使用抗坏血酸、硫醇或黄素限制，确定羟胺或亚硝基还原的改变是否影响对SMX代谢物的免疫原性反应。最后，我们将在一项淋巴恶性肿瘤免疫功能低下患者的前瞻性研究中确定羟胺或亚硝基还原受损是否是SMX超敏反应的危险因素。这些研究将推进我们对SMX超敏反应机制的理解，并将表征异生物质减少的新直接途径中的个体变异性，对许多化合物的反应具有临床意义，包括偕胺肟前药和芳胺致癌物，以及SMX。相关性：这些研究将帮助我们更好地了解导致“磺胺药物”过敏的个体风险因素，通过了解磺胺药物在不同人群中代谢的差异。这些研究的最终目的是找到更好的方法来预防这些不良反应。

DESCRIPTION (provided by applicant): 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.