Role of glutathione in prevention of acetaminophen-induced hepatotoxicity by N-acetyl-L-cysteine in vivo: studies with N-acetyl-D-cysteine in mice.
Role of glutathione in prevention of acetaminophen-induced hepatotoxicity by N-acetyl-L-cysteine in vivo: studies with N-acetyl-D-cysteine in mice.
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发表时间：
1986-07
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通讯作者：
George B. Corcoran;B. Wong
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作者：
George B. Corcoran;B. Wong
许多共价结合估计值由于有缺陷的标准化而错误地低，这一发现揭示了N-乙酰基-L-半胱氨酸对对乙酰氨基酚肝毒性的保护通常伴随着芳基化下降50 - 80%。谷胱甘肽升高可能是抑制共价结合的原因，但在N-乙酰-L-半胱氨酸治疗后，从未在体内证实过高于正常浓度，或与其他可能的保肝作用（包括解毒剂直接还原毒性对乙酰氨基酚代谢物）充分分离。这使我们将解毒剂的常规L-异构体与其非生理性立体异构体N-乙酰-D-半胱氨酸进行比较，因为后者应该能够减少毒性代谢物，但不能刺激谷胱甘肽的生物合成。然而，口服联合给予N-乙酰-D-半胱氨酸（1200 mg/kg）未能防止血清丙氨酸氨基转移酶活性升高，未能减少肝细胞坏死，未能阻断毒性代谢物与肝细胞蛋白的共价结合，也未能防止500 mg/kg对乙酰氨基酚引起的肝谷胱甘肽耗竭。N-乙酰-L-半胱氨酸成功地降低了对乙酰氨基酚肝毒性的这些指标，同时使肝脏谷胱甘肽浓度比对照值高2-3倍。L-异构体还增加了谷胱甘肽衍生的对乙酰氨基酚代谢物的尿排泄，而D-异构体仅增加了对乙酰氨基酚硫酸盐的排泄，并逆转了对乙酰氨基酚半胱氨酸相对于巯基尿酸缀合物的习惯优势。N-乙酰-D-半胱氨酸的肝脏摄取反映在器官浓度比L-异构体高7倍。（250字处删节）
The revelation that many covalent binding estimates are falsely low due to flawed normalization discloses that protection by N-acetyl-L-cysteine against acetaminophen hepatotoxicity is accompanied routinely by a 50 to 80% decline in arylation. Elevated glutathione may be responsible for inhibiting covalent binding but above-normal concentrations have never been demonstrated in vivo after N-acetyl-L-cysteine treatment or separated adequately from other possible hepatoprotective actions including direct reduction of the toxic acetaminophen metabolite by the antidote. This led us to compare the conventional L-isomer of the antidote to its nonphysiologic stereoisomer, N-acetyl-D-cysteine, because the latter should be capable of reducing the toxic metabolite but not of stimulating glutathione biosynthesis. Oral coadministration of N-acetyl-D-cysteine (1200 mg/kg), however, failed in preventing the elevation of serum alanine aminotransferase activity, in decreasing hepatocellular necrosis, in interdicting covalent binding of the toxic metabolite to hepatocellular proteins and in preventing the depletion of liver glutathione caused by 500 mg/kg of acetaminophen. N-acetyl-L-cysteine succeeded in decreasing these measures of acetaminophen hepatotoxicity while driving liver glutathione concentrations 2-3 fold above control values. The L-isomer also increased urinary excretion of glutathione-derived acetaminophen metabolites whereas the D-isomer increased only acetaminophen sulfate excretion and reversed the customary predominance of acetaminophen cysteine over the mercapturic acid conjugate. Liver uptake of N-acetyl-D-cysteine was reflected in organ concentrations 7-fold higher than noted for the L-isomer.(ABSTRACT TRUNCATED AT 250 WORDS)