Nitogen reduction and xenobiotic response

描述(申请人提供)：羟胺和亚硝基代谢物与磺胺甲恶唑(SMX)和其他芳胺类药物的不良反应的发病机制有关。羟胺会自发氧化成反应性亚硝基代谢物，在SMX的情况下，这会引发迟发性超敏反应。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首选药物。关于SMX过敏症的代谢危险因素的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。我们最近已经证明，羟胺可以被黄素蛋白NADH细胞色素b5还原酶(B5R)和血红蛋白细胞色素b5(Cytb5)解毒，这是通过一种新的、直接的异种还原途径实现的。我们还表明，除了硫醇之外，抗坏血酸还提供了亚硝基还原的主要途径。我们的总体假设是，羟胺或亚硝基还原受损使患者容易对芳胺化合物产生不良反应，如对SMX过敏。我们将首先通过表征羟胺还原的可变性及其与人类b5R或Cytb5基因多态的关系来解决这一假说。接下来，我们将使用抗坏血酸、硫醇或黄素限制豚鼠模型，确定羟胺或亚硝基还原的变化是否影响对SMX代谢物的免疫原性反应。最后，我们将在一项针对免疫受损的淋巴系统恶性肿瘤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。这些研究将促进我们对SMX过敏机制的理解，并将表征一种新的直接异物还原途径中的个体差异，对除SMX之外的许多化合物的反应具有临床意义，包括胺肟类前体药物和芳胺类致癌物质。相关性：这些研究将通过了解不同人对磺胺类药物代谢方式的差异，帮助我们更好地了解导致人们对磺胺类药物过敏的个体风险因素。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。

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.