Glutathione efflux from perfused rat liver after phenobarbital treatment, during drug oxidations, and in selenium deficiency.
Glutathione efflux from perfused rat liver after phenobarbital treatment, during drug oxidations, and in selenium deficiency.
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苯巴比妥治疗后、药物氧化期间和缺硒时，谷胱甘肽从灌注的大鼠肝脏中流出。
DOI：
10.1111/j.1432-1033.1978.tb20902.x
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发表时间：
1978
期刊：
影响因子：
--
通讯作者：
Christian Waydhas
中科院分区：
文献类型：
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作者：
Helmut Sies;Gianna;Raymond F. Burk;Christian Waydhas
1
本文研究了在不同代谢条件下，还原型谷胱甘肽（GSH）和氧化型谷胱甘肽（GSSG）从灌流的大鼠肝脏中的流出。
2
在37 °C的非再循环无血红蛋白灌注中，每克肝脏的谷胱甘肽流出量为14 nmol/min，其中GSH为12 nmol/min，GSSG为1 nmol/min。在苯巴比妥预处理的大鼠肝脏中观察到类似的速率。这被解释为表明文献中描述的分离的微粒体膜的H2 O2产生能力增加在完整细胞中未检测到，因为来自其他细胞内来源（例如，苄胺）的H2 O2产生导致额外的GSSG流出。
同样，谷胱甘肽过氧化物酶低的硒缺乏大鼠（补硒对照组的8%，H2 O2作为底物）的肝脏谷胱甘肽释放与对照组没有显着差异。这一观察结果与Burk等人[J. Biol. Chem. 253，43-46]的观察结果相反，后者发现暴露于硒缺乏更长时间的大鼠肝脏中谷胱甘肽释放增加2倍。因此，脂质过氧化速率升高可能发生在更严重的缺硒，其中因素以外的低GSH过氧化物酶活性可能有助于影响。
3
在依赖于细胞色素P-450的药物氧化过程中，使用氨基比林、乙基吗啡和己巴比妥作为底物，在苯巴比妥预处理的大鼠肝脏中观察到GSSG流出率增加。半最大氨基比林浓度为GSSG流出，0.1-0.2 mM，类似于额外的O2摄取，但低于氨基比林N-去甲基化，0.5-0.6 mM。氨基比林依赖的GSSG流出也存在于肝脏中的硒缺乏大鼠，而H2 O2依赖或苄胺依赖的GSSG流出被废除。这些结果不支持在完整细胞中药物氧化期间额外产生游离H2 O2。未来的研究必须评估谷胱甘肽氧化是否通过活性药物代谢物或脂质过氧化速率增加或谷胱甘肽还原酶的反平衡伴随NADPH水平降低而发生。
1
The efflux of reduced (GSH) and oxidized (GSSG) glutathione from perfused rat liver was studied in different metabolic conditions.
2
At 37 °C in non-recirculating hemoglobin-free perfusion, efflux of glutathione per gram of liver was 14 nmol/min, of which GSH was 12 nmol/min and GSSG 1 nmol/min. Similar rates were observed in livers from phenobarbital-pretreated rats. This is interpreted to indicate that the increased capacity for H2O2 production described in the literature for isolated microsomal membranes is not detectably realized in the intact cell, since H2O2 production from other intracellular sources, e.g. benzylamine, leads to an extra GSSG efflux.
Similarly, the glutathione release from livers of selenium-deficient rats low in GSH peroxidase (8% of the selenium-supplemented controls, H2O2 as substrate) was not significantly different from the controls. This observation contrasts with that of Burk et al. [J. Biol. Chem. 253, 43–46] who found a 2-fold increase in glutathione release in livers from rats exposed to selenium-deficiency for a more extended time period. Thus, elevated rates of lipid peroxidation may occur in more severe selenium-deficiency where factors other than a low GSH peroxidase activity may contribute to the effect.
3
An increased rate of GSSG efflux was observed in livers from phenobarbital-pretreated rats during drug oxidations dependent on cytochrome P-450, using aminopyrine, ethylmorphine and hexobarbital as substrates. Half-maximal aminopyrine concentration for GSSG efflux, 0.1–0.2 mM, was similar to that of the extra O2 uptake but lower than that for aminopyrine N-demethylation, 0.5–0.6 mM. Aminopyrine-dependent GSSG efflux was present also in livers from selenium-deficient rats whereas H2O2-dependent or benzylamine-dependent GSSG efflux was abolished. These results do not support extra production of free H2O2 during drug oxidation in the intact cell. Future investigations must evaluate whether glutathione oxidation occurs by reactive drug metabolites or by an enhanced rate of lipid peroxidation, or by back-equilibration of glutathione reductase concomitant with the decreased NADPH levels.