Foreman J W, Bowring M A, Lee J, States B, Segal S
Division of Biochemical Development and Molecular Diseases, Children's Hospital of Philadelphia, PA 19104.
Metabolism. 1987 Dec;36(12):1185-91. doi: 10.1016/0026-0495(87)90246-0.
The effect of cystine dimethylester on the renal handling of phosphate, glucose, alpha-amino nitrogen, amino acids, and protein in vivo and on the uptake of lysine, glycine, taurine, and alpha-methyl glucoside by isolated renal tubules in vitro was studied in adult male rats. Parenteral administration of 400 mumol twice a day for four days of cystine dimethylester led to an increased urine volume, and excretion of phosphate, glucose, alpha-amino nitrogen, and the amino acids glutamine, proline, alanine, 1/2 cystine, ornithine, lysine, histidine, and glycine. Cystine dimethylester treatment did not affect the creatine clearance nor were any renal anatomic abnormalities noted. Intracellular cysteine, but not cystine, was increased in the kidney after the four days of treatment. Pre-incubation of isolated renal tubules with 2 mmol/L cystine dimethylester for ten minutes markedly inhibited the uptake of 0.025 mmol/L lysine, 0.1 mmol/L glycine, 0.01 mmol/L taurine, and 2 mmol/L alpha-methyl glucoside. Incubation with 2 mmol/L cystine dimethylester for ten minutes did not affect the ability of the renal tubule to exclude trypan blue dye, although longer incubation times did lead to significant staining. The intracellular cystine concentration of the renal tubule did rise significantly after incubation with cystine dimethylester, a biochemical correlate of the human disease cystinosis. These studies indicate that cystine dimethylester can induce an experimental form of the Fanconi syndrome both in vivo and in vitro and offers a new model for investigating the mechanisms underlying this enigmatic disorder.
在成年雄性大鼠中，研究了胱氨酸二甲酯对体内磷酸盐、葡萄糖、α-氨基氮、氨基酸和蛋白质的肾脏处理，以及对体外分离的肾小管摄取赖氨酸、甘氨酸、牛磺酸和α-甲基葡萄糖苷的影响。每天两次肠胃外给予400 μmol胱氨酸二甲酯，持续四天，导致尿量增加，以及磷酸盐、葡萄糖、α-氨基氮和氨基酸谷氨酰胺、脯氨酸、丙氨酸、1/2胱氨酸、鸟氨酸、赖氨酸、组氨酸和甘氨酸的排泄增加。胱氨酸二甲酯治疗不影响肌酐清除率，也未观察到任何肾脏解剖学异常。治疗四天后，肾脏中的细胞内半胱氨酸增加，但胱氨酸未增加。将分离的肾小管与2 mmol/L胱氨酸二甲酯预孵育十分钟，可显著抑制0.025 mmol/L赖氨酸、0.1 mmol/L甘氨酸、0.01 mmol/L牛磺酸和2 mmol/Lα-甲基葡萄糖苷的摄取。与2 mmol/L胱氨酸二甲酯孵育十分钟不影响肾小管排除台盼蓝染料的能力，尽管更长的孵育时间确实会导致显著染色。与胱氨酸二甲酯孵育后，肾小管的细胞内胱氨酸浓度确实显著升高，这是人类疾病胱氨酸病的生化相关指标。这些研究表明，胱氨酸二甲酯在体内和体外均可诱导范科尼综合征的实验形式，并为研究这种神秘疾病的潜在机制提供了一个新模型。
