Griffith O W
J Biol Chem. 1981 Dec 10;256(23):12263-8.
Previous studies with cystinuric dogs and humans have demonstrated that the amount of cystine excreted in the urine is, in some cases, larger than the amount of cystine removed from the plasma by glomerular filtration. It was concluded that the kidney must secrete cystine into the renal tubule. The present studies indicate that renal glutathione turnover constitutes a mechanism of cystine secretion which may account for a large fraction of the cystine burden in the mouse renal tubule. Mice administered L-arginine or L-lysine, inhibitors of cystine transport, excrete large amounts of cystine in their urine (approximately 15 mumol of cystine/mg of creatine). If the mice are pretreated with buthionine sulfoximine, an inhibitor of glutathione biosynthesis, glutathione turnover is substantially decreased, and the arginine- or lysine-induced cystinuria is reduced by 43 to 55%. The plasma cystine concentration following arginine or lysine administration is reduced less than 15% by buthionine sulfoximine. These findings suggest the in vivo operation of a cycle in which glutathione, synthesized from cysteine intracellularly, is transported into the tubule and oxidized to glutathione disulfide. Subsequent breakdown of glutathione disulfide by gamma-glutamyl transpeptidase and dipeptidase releases cystine within the tubule. In the absence of cystine transport defects or inhibitors, cystine is reabsorbed and reduced intracellularly to cysteine.
先前对胱氨酸尿症犬类和人类的研究表明，在某些情况下，尿液中排出的胱氨酸量大于肾小球滤过从血浆中清除的胱氨酸量。由此得出结论，肾脏必定会将胱氨酸分泌到肾小管中。目前的研究表明，肾脏谷胱甘肽周转构成了一种胱氨酸分泌机制，这可能是小鼠肾小管中大部分胱氨酸负荷的原因。给予L - 精氨酸或L - 赖氨酸（胱氨酸转运抑制剂）的小鼠，尿液中会排出大量胱氨酸（约15 μmol胱氨酸/毫克肌酸）。如果用谷胱甘肽生物合成抑制剂丁硫氨酸亚砜胺预处理小鼠，谷胱甘肽周转会大幅减少，精氨酸或赖氨酸诱导的胱氨酸尿症会降低43%至55%。丁硫氨酸亚砜胺使精氨酸或赖氨酸给药后血浆胱氨酸浓度降低不到15%。这些发现表明，体内存在一个循环，即细胞内由半胱氨酸合成的谷胱甘肽被转运到肾小管并氧化为谷胱甘肽二硫化物。随后，谷胱甘肽二硫化物被γ-谷氨酰转肽酶和二肽酶分解，在肾小管内释放出胱氨酸。在没有胱氨酸转运缺陷或抑制剂的情况下，胱氨酸被重新吸收并在细胞内还原为半胱氨酸。
