权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Nitogen reduction and xenobiotic response

氮减少和外源性反应

基本信息

批准号：
8052011
负责人：
LAUREN A TREPANIER
金额：
$ 25.02万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-28 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8052011
关键词：
Abbreviations Address Adverse reactions Alkaline Phosphatase Aromatic Amines Ascorbic Acid Biological Assay Buthionine Sulfoximine Carcinogens Cavia Cells Clinical Code Cytochromes Cytochromes b5 DNA Resequencing Dapsone Delayed Hypersensitivity Development Drug Hypersensitivity Ethnic group Flavin Mononucleotide Flavin-Adenine Dinucleotide Flavins Flavoproteins Genetic Polymorphism Genomics Glutathione Goals Hemeproteins High Pressure Liquid Chromatography Highly Active Antiretroviral Therapy Human Hydroxylamine Hypersensitivity Immunocompromised Host Individual Infection Lead Learning Leukocytes Liver Luciferases Malignant lymphoid neoplasm Metabolic Biotransformation Metabolism Modeling N-hydroxy-4-aminobiphenyl NADH Nicotinamide adenine dinucleotide Opportunistic Infections Oxidoreductase Parents Pathogenesis Pathway interactions Patients Performance Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Prevalence Prevention Procainamide Prodrugs Promoter Regions Prospective Studies Reaction Reporter Research Personnel Risk Risk Factors Sampling Serum Single Nucleotide Polymorphism Source Sulfamethoxazole Sulfhydryl Compounds Surrogate Markers T cell response Testing Tissues Trimethoprim-Sulfamethoxazole Xenobiotics adduct ascorbate cofactor cytochrome b5 reductase immunogenic immunogenicity metabolic abnormality assessment novel oxidation prevent programs response sulfa drug sulfamethoxazole hydroxylamine

项目摘要

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.

项目摘要：羟胺和亚硝基代谢物与糖尿病的发病机制有关磺胺甲恶唑（SMX）和其他芳基胺药物的不良反应。羟胺自发产生氧化成活性亚硝基代谢物，就 SMX 而言，可引发迟发型超敏反应反应。这些超敏反应干扰了 SMX 的有效使用，SMX 是免疫功能低下患者预防机会性感染的选择。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可被黄素蛋白 NADH 细胞色素 b5 还原酶 (b5R) 解毒，血红素蛋白细胞色素 b5 (cyt b5)，通过一种新颖、直接的外源性还原途径。我们还有研究表明，除了硫醇之外，抗坏血酸还提供了亚硝基还原的主要途径。我们的整体假设羟胺或亚硝基还原受损使患者容易出现不良反应芳胺化合物，例如对 SMX 过敏。我们将首先解决这个假设表征羟胺还原的变异性及其与 b5R 或遗传多态性的关系人体中的细胞色素b5。接下来我们将确定羟胺或亚硝基还原的改变是否会影响在豚鼠中使用抗坏血酸、硫醇或黄素限制对 SMX 代谢物产生免疫原性反应模型。最后，我们将确定羟胺或亚硝基还原受损是否是一个危险因素 SMX 超敏反应，针对患有淋巴恶性肿瘤的免疫功能低下患者的一项前瞻性研究。这些研究将增进我们对 SMX 超敏反应背后机制的理解，并将表征外源性物质减少的新型直接途径中的个体差异，并具有临床意义用于响应许多化合物，包括偕胺肟前药和芳基胺致癌物，此外至 SMX。相关性：这些研究将帮助我们更好地了解导致“磺胺类药物”的个体危险因素通过了解不同的磺胺类药物代谢方式的差异，来了解人们的过敏情况人们。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。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cytochrome b5 and NADH cytochrome b5 reductase: genotype-phenotype correlations for hydroxylamine reduction.

DOI：
10.1097/fpc.0b013e3283343296
发表时间：
2010-01
期刊：
Pharmacogenetics and genomics
影响因子：
2.6
作者：
Sacco JC;Trepanier LA
通讯作者：
Trepanier LA

Evaluation of the clinical, immunologic, and biochemical effects of nitroso sulfamethoxazole administration to dogs: a pilot study.

评估亚硝基磺胺甲恶唑对狗的临床、免疫和生化作用：一项初步研究。

DOI：
10.1016/j.tox.2004.11.009
发表时间：
2005
期刊：
Toxicology.
影响因子：
0
作者：
Lavergne,SidonieN;Volkman,ErinM;Maki,JenniferE;Yoder,AndreaR;Trepanier,LaurenA
通讯作者：
Trepanier,LaurenA

Plasma ascorbate deficiency is associated with impaired reduction of sulfamethoxazole-nitroso in HIV infection.

血浆抗坏血酸缺乏与 HIV 感染中磺胺甲恶唑亚硝基还原受损有关。

DOI：
10.1097/00126334-200408150-00007
发表时间：
2004
期刊：
Journal of acquired immune deficiency syndromes (1999)
影响因子：
0
作者：
Trepanier,LaurenA;Yoder,AndreaR;Bajad,Sunil;Beckwith,MichelleD;Bellehumeur,JenniferL;Graziano,FrankM
通讯作者：
Graziano,FrankM

Polymorphisms in the carcinogen detoxification genes CYB5A and CYB5R3 and breast cancer risk in African American women.

DOI：
10.1007/s10552-014-0454-7
发表时间：
2014-11
期刊：
Cancer causes & control : CCC
影响因子：
0
作者：
Blanke KL;Sacco JC;Millikan RC;Olshan AF;Luo J;Trepanier LA
通讯作者：
Trepanier LA

Anti-myeloperoxidase and anti-cathepsin G antibodies in sulphonamide hypersensitivity.

磺胺超敏反应中的抗髓过氧化物酶和抗组织蛋白酶 G 抗体。

DOI：
10.1111/j.1365-2222.2007.02845.x
发表时间：
2008
期刊：
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
影响因子：
0
作者：
Lavergne,SN;Drescher,NJ;Trepanier,LA
通讯作者：
Trepanier,LA