CYSTINURIA: METABOLISM OF THE DISULFIDE OF CYSTEINE AND HOMOCYSTEINE*

Abstract

The asymmetrical disulfide of L-cysteine and L-homocysteine is uniformly excreted in the urine of patients with cystinuria. This amino acid was found in the urine of a dog with cystinuria and cystine stone disease. The asymmetrical disulfide was occasionally seen in the urine of patients with generalized amino-aciduria because of the Fanconi syndrome or Wilson''s disease. The amount was increased by feeding L-methionine to 2 patients with the Fanconi syndrome. The disulfide was presumptively demonstrated in the plasma of patients with advanced renal insufficiency. These experiments demonstrated that the mixed disulfide has a wide distribution in trace amounts. The asymmetrical disulfide, labeled with S35, was excreted by a patient with cystinuria after administration of L-methionine-S35. The homocysteine sulfur was initially of higher specific activity than the cysteine sulfur. Intravenously administered mixed disulfide was metabolized by a rat and apparently by a patient with cystinuria. It is proposed that the mixed disulfide arises through a mechanism whereby cysteine combines with homocysteine. The data suggest that the amino acid may be a normal metabolite. In cystinuria and in the generalized amino-acidurias, mixed disulfide seems to be cleared rapidly from the plasma by the kidney and appears in the urine. Determination of renal venous and arterial concentrations of amino acids in cystinuria revealed that cystine is extracted to a degree similar to amino acids not considered to be involved in cystinuria. The plasma cysteine, however, is extracted to a high degree. This study suggests that urinary cystine arises largely from plasma cysteine in cystinuria. The asymmetrical disulfide also appears to be extracted to a high degree, although renal production of the amino acid is not ruled out.