Plasma ascorbate deficiency is associated with impaired reduction of sulfamethoxazole-nitroso in HIV infection.
Plasma ascorbate deficiency is associated with impaired reduction of sulfamethoxazole-nitroso in HIV infection.
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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
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
Graziano,FrankM
中科院分区：
文献类型：
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作者：
Trepanier,LaurenA;Yoder,AndreaR;Bajad,Sunil;Beckwith,MichelleD;Bellehumeur,JenniferL;Graziano,FrankM
目的：这些研究的目的是确定抗坏血酸缺乏症在HIV感染中的作用，磺胺甲恶唑-亚硝基，代谢物被认为是介导磺胺类药物过敏反应的缺陷解毒：五十一名HIV感染者和26名健康志愿者进行了评估。获得维生素补充剂的历史，并收集血液样本用于测定血浆抗坏血酸、脱氢抗坏血酸和半胱氨酸浓度，红细胞谷胱甘肽浓度，以及血浆磺胺甲恶唑-亚硝基体外还原。（29.5±22.3 μM）高于健康受试者（54.8±22.3 μM; P= 0.0005）和每天服用500-1000 mg抗坏血酸盐的患者（82.5±26.3 μM; P< 0.0001）。血浆抗坏血酸缺乏与磺胺甲恶唑-亚硝基还原成其羟胺的受损密切相关（r= 0.60，P< 0.0001），在体外还原过程中，血浆抗坏血酸的损失与亚硝基还原量密切相关（r= 0.70，P< 0.0001）。离体添加抗坏血酸使该还原途径正常化。HIV阳性患者的红细胞谷胱甘肽浓度（0.98±0.32 mM）显着低于健康受试者（1.45±0.49 mM; P= 0.001），但这一发现与抗坏血酸补充无关。患者的血浆半胱氨酸浓度（8.4±3.9 μM）有低于对照组（10.3±4.3 μM）的趋势，但这种趋势同样与抗坏血酸补充无关。脱氢抗坏血酸浓度在HIV阳性患者中（7.4±10.5%）并不显著高于健康对照组（4.0±6.2%），即使在服用抗坏血酸盐的患者亚组中（8.4±9.4%）。结论：抗坏血酸缺乏在HIV阳性患者中很常见，与磺胺甲恶唑-亚硝基解毒功能受损有关，磺胺超敏反应中疑似的近毒素。每日服用抗坏血酸补充剂（500-1000毫克）的患者达到了高血浆抗坏血酸浓度，并没有表现出这种解毒缺陷。抗坏血酸缺乏（或补充）与谷胱甘肽或半胱氨酸浓度的变化无关。这些数据表明，抗坏血酸缺乏，独立的巯基状态，可能是一个重要的决定因素，受损的药物解毒HIV感染。
Objective:The objective of these studies was to determine the role of ascorbate deficiency in HIV infection in the defective detoxification of sulfamethoxazole-nitroso, the metabolite thought to mediate sulfonamide hypersensitivity reactions.Methods:Fifty-one HIV-infected patients and 26 healthy volunteers were evaluated. Vitamin supplementation histories were obtained, and blood samples were collected for determination of plasma ascorbate, dehydroascorbate, and cysteine concentrations, erythrocyte glutathione concentrations, and plasma reduction of sulfamethoxazole-nitroso in vitro.Results:Plasma ascorbate concentrations were significantly lower in HIV-positive patients not taking vitamin supplements (29.5±22.3 μM) than in healthy subjects (54.8±22.3 μM; P= 0.0005) and patients taking 500–1000 mg of ascorbate daily (82.5±26.3 μM; P< 0.0001). Plasma ascorbate deficiency was strongly correlated with impaired reduction of sulfamethoxazole-nitroso to its hydroxylamine (r= 0.60, P< 0.0001), and during in vitro reduction, the loss of plasma ascorbate was strongly associated with the amount of nitroso reduced (r= 0.70, P< 0.0001). Ascorbate added ex vivo normalized this reduction pathway. Erythrocyte glutathione concentrations were significantly lower in HIV-positive patients (0.98±0.32 mM) than in healthy subjects (1.45±0.49 mM; P= 0.001), but this finding was unrelated to ascorbate supplementation. There was trend toward lower plasma cysteine concentrations in patients (8.4±3.9 μM) than in controls (10.3±4.3 μM), but this trend was similarly unrelated to ascorbate supplementation. Dehydroascorbate concentrations were not significantly higher in HIV-positive patients (7.4±10.5%) than in healthy controls (4.0±6.2%), even in the subset of patients taking ascorbate (8.4±9.4%).Conclusions:Ascorbate deficiency is common in HIV-positive patients and is associated with impaired detoxification of sulfamethoxazole-nitroso, the suspected proximate toxin in sulfonamide hypersensitivity. Patients taking daily ascorbate supplements (500–1000 mg) achieved high plasma ascorbate concentrations and did not show this detoxification defect. Ascorbate deficiency (or supplementation) was not associated with changes in glutathione or cysteine concentrations. These data suggest that ascorbate deficiency, independent of thiol status, may be an important determinant of impaired drug detoxification in HIV infection.