Sato K, Robbins J
Endocrinology. 1981 Sep;109(3):844-52. doi: 10.1210/endo-109-3-844.
To elucidate the recently advanced hypothesis that glutathione [L-gamma-glutamyl-L-cysteinyl glycine (GSH)] regulates deiodinating enzyme activities, accounting for the decreased conversion of T4 to T3 in the liver of fetal and starved animals, we investigated thyroid hormone metabolism in GSH-depleted neoplastic and normal hepatocytes. In monkey hepatocarcinoma cells, intracellular total GSH decreased below 10% of the control value (approximately 25 micrograms/mg protein) when cells were grown for 44 h in medium deficient in cystine and methionine or in cystine alone. The latter finding indicated that transsulfuration from methionine to cysteine was defective in these neoplastic cells. In primary cultured adult rat hepatocytes, on the other hand, the transsulfuration pathway was intact, and total GSH decreased below 10% of control (approximately 20 micrograms/mg protein) only in cells grown in cystine- and methionine-deficient medium. In both cell types, the oxidized GSH fraction remained constant (2-5% of total). Incubation with 125I-labeled T4 and T3, followed by chromatography, was used to evaluate 5-deiodination in hepatocarcinoma cells and both 5- and 5'-deiodination in normal hepatocytes. Deiodination was not decreased by GSH deficiency in either case, but was actually increased in hepatocarcinoma cells. This resulted from an increase in the Vmax of 5-deiodinase related to growth arrest. Diamide at 2 mM reversibly inhibited both 5'- and 5'-deiodination in rat hepatocytes, accompanied by decreased total GSH as well as increased GSH disulfide (27% of total). The data suggest that GSH is so abundant in the liver that hepatocytes can tolerate a greater than 90% decrease in intracellular concentration without any change in thyroid hormone deiodination and indicate that altered thyroid hormone metabolism in the fetus and in starvation cannot be accounted for by a decreased hepatic GSH concentration.
为了阐明最近提出的一个假说，即谷胱甘肽[L-γ-谷氨酰-L-半胱氨酰甘氨酸（GSH）]调节脱碘酶活性，这可以解释胎儿和饥饿动物肝脏中T4向T3转化减少的现象，我们研究了谷胱甘肽耗竭的肿瘤性和正常肝细胞中的甲状腺激素代谢。在猴肝癌细胞中，当细胞在缺乏胱氨酸和蛋氨酸或仅缺乏胱氨酸的培养基中培养44小时时，细胞内总谷胱甘肽降至对照值（约25微克/毫克蛋白质）的10%以下。后一发现表明，这些肿瘤细胞中从蛋氨酸到半胱氨酸的转硫途径存在缺陷。另一方面，在原代培养的成年大鼠肝细胞中，转硫途径是完整的，只有在缺乏胱氨酸和蛋氨酸的培养基中生长的细胞中，总谷胱甘肽才降至对照值（约20微克/毫克蛋白质）的10%以下。在这两种细胞类型中，氧化型谷胱甘肽部分保持恒定（占总量的2-5%）。用125I标记的T4和T3孵育，然后进行色谱分析，以评估肝癌细胞中的5-脱碘作用以及正常肝细胞中的5-和5'-脱碘作用。在这两种情况下，谷胱甘肽缺乏均未使脱碘作用降低，但在肝癌细胞中实际上有所增加。这是由于与生长停滞相关的5-脱碘酶的Vmax增加所致。2 mM的二酰胺可逆地抑制大鼠肝细胞中的5'-和5'-脱碘作用，同时总谷胱甘肽减少以及谷胱甘肽二硫化物增加（占总量的27%）。数据表明，肝脏中谷胱甘肽含量非常丰富，以至于肝细胞能够耐受细胞内浓度降低9０%以上而甲状腺激素脱碘作用无任何变化，这表明胎儿和饥饿状态下甲状腺激素代谢的改变不能用肝脏谷胱甘肽浓度降低来解释。
