Although corticosteroids are effective in the treatment of hypercalciuria and hypercalcemia in chronic sarcoidosis, complications of their long-term use frequently limit therapy. We studied the efficacy of chloroquine in two patients with sarcoidosis who were unable to tolerate the dosage of corticosteroids required to control hypercalciuria and prevent the formation of renal stones. Over a three-year period, each patient received a 6-month and a 10-month course of oral chloroquine phosphate (500 mg per day) while continuing to receive corticosteroids at a fixed dose. Chloroquine therapy was associated with a significant reduction in levels of serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and urinary calcium. We observed a direct correlation between serum 1,25-(OH)2D levels and 24-hour urinary calcium excretion, supporting the hypothesis that excessive serum 1,25-(OH)2D is responsible for the hypercalciuria in sarcoidosis. Serum levels of 25-hydroxyvitamin D (25-(OH)D) did not change with therapy, suggesting that chloroquine may act by inhibiting the conversion of 25-(OH)D to 1,25-(OH)2D. Current dosage guidelines and ophthalmologic-surveillance techniques, which allow chloroquine to be administered with little risk of retinopathy, should permit an expanded role for this agent in the treatment of the calcium abnormalities of sarcoidosis.

The hypophosphatemic (Hyp) mouse, a murine homologue of human X-linked hypophosphatemic rickets, is characterized by renal defects in brush border membrane phosphate transport and vitamin %3 metabolism. The present study was undertaken to examine whether elevated renal 25-hydroxyvitamin D3-24-hydroxylase

Side-chain oxidation of vitamin D is an important degradative pathway. In the present study we compared the enzymes involved in side-chain oxidation in normal and Hyp mouse kidney. Homogenates of normal mouse kidney catalyze the conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3, 24-oxo-25-hydroxyvitamin D3 and 24-oxo-23,25-dihydroxyvitamin D3. After subcellular fractionation, total side-chain oxidative activity, estimated by the sum of the three products synthesized per milligram protein under initial rate conditions, coincided with the mitochondrial enzyme marker succinate-cytochrome-c reductase. Treatment of normal mice with 1,25-dihydroxyvitamin D3 (1.5 ng/g) resulted in an eightfold increase in mitochondrial enzyme activity, with no change in apparent Km but a significant rise in Vmax. With 24,25-dihydroxyvitamin D3 as the substrate, normal renal mitochondria produced 24-oxo-25-hydroxyvitamin D3 and 24-oxo-23,25-dihydroxyvitamin D3, and the synthesis of these metabolites could be increased sixfold by pretreatment with 1,25-dihydroxyvitamin D3. In the Hyp mouse, the side-chain oxidation pathway showed similar subcellular distribution of enzyme activity. However, product formation from 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 was twofold greater in mutant than in normal mitochondria. Furthermore, 1,25-dihydroxyvitamin D3 pretreatment of Hyp mice resulted in a 3.4-fold increase over basal metabolism of both 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3. These results demonstrate that (i) kidneys from normal and Hyp mice possess basal and 1,25-dihydroxyvitamin D3 inducible enzyme system(s) in the mitochondrial fraction, which catalyze the side-chain oxidation of 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3, and (ii) the Hyp mutation appears to perturb the renal metabolism of both substrates only in the basal state.