Trepanier Lauren A, Yoder Andrea R, Bajad Sunil, Beckwith Michelle D, Bellehumeur Jennifer L, Graziano Frank M
Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin--Madison, Madison, WI 53706-1102, USA.
J Acquir Immune Defic Syndr. 2004 Aug 15;36(5):1041-50. doi: 10.1097/00126334-200408150-00007.
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.
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.
Plasma ascorbate concentrations were significantly lower in HIV-positive patients not taking vitamin supplements (29.5 +/- 22.3 microM) than in healthy subjects (54.8 +/- 22.3 microM; P = 0.0005) and patients taking 500-1000 mg of ascorbate daily (82.5 +/- 26.3 microM; 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 microM) than in controls (10.3+/-4.3 microM), 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%).
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.
这些研究的目的是确定抗坏血酸缺乏在HIV感染中对磺胺甲恶唑-亚硝基（被认为介导磺胺类药物超敏反应的代谢产物）解毒缺陷的作用。
对51例HIV感染患者和26名健康志愿者进行了评估。获取了维生素补充史，并采集血样以测定血浆抗坏血酸、脱氢抗坏血酸和半胱氨酸浓度、红细胞谷胱甘肽浓度以及体外血浆中磺胺甲恶唑-亚硝基的还原情况。
未服用维生素补充剂的HIV阳性患者的血浆抗坏血酸浓度（29.5±22.3微摩尔/升）显著低于健康受试者（54.8±22.3微摩尔/升；P = 0.0005）和每天服用500 - 1000毫克抗坏血酸的患者（82.5±26.3微摩尔/升；P < 0.0001）。血浆抗坏血酸缺乏与磺胺甲恶唑-亚硝基还原为其羟胺的能力受损密切相关（r = 0.60，P < 0.0001），并且在体外还原过程中，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）。体外添加抗坏血酸可使该还原途径恢复正常。HIV阳性患者的红细胞谷胱甘肽浓度（0.98±0.32毫摩尔/升）显著低于健康受试者（1.45±0.49毫摩尔/升；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微摩尔/升）有低于对照组（10.3±4.3微摩尔/升）的趋势，但这一趋势同样与抗坏血酸补充无关。HIV阳性患者的脱氢抗坏血酸浓度（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的患者亚组中（8.4±9.4%）也是如此。
抗坏血酸缺乏在HIV阳性患者中很常见，并且与磺胺甲恶唑-亚硝基解毒缺陷有关，磺胺甲恶唑-亚硝基是磺胺类药物超敏反应中疑似的直接毒素。每天服用抗坏血酸补充剂（500 - 1000毫克）的患者血浆抗坏血酸浓度较高，且未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，独立于硫醇状态的抗坏血酸缺乏可能是HIV感染中药物解毒受损的一个重要决定因素。
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