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Effect of the X-Linked Hyp Mutation and Vitamin D Status on Induction of Renal 25-Hydroxyvitamin D₃-24-Hydroxylase^*

MRC Genetics Group, McGill University-Montreal Children’s Hospital Research Institute Montreal, Quebec, Canada H3H 1P3
Departments of Medicine and Biochemistry, Queen’s University Kingston, Ontario, Canada K7L 3N6

Address requests for reprints to: Dr. Harriet S. Tenenhouse, MRC Genetics Group, McGill University-Montreal Children’s Hospital Research Institute, 2300 Tupper Street, Montreal, Quebec H3H 1P3, Canada.

Abstract

The present study was undertaken to evaluate the response of Hyp mice to regulators known to inhibit renal 25-hydroxyvitamin D3-l-hydroxylase (1-hydroxylase) and stimulate renal 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase). Renal mitochondrial metabolism of 25-hydroxyvitamin D3 (25OHD₃) was initially examined in vitamin D- and calciumdeprived normal and mutant mice (with no detectable 24-hydroxylase) treated with either calcium, 1,25-dihydroxyvitamin D3 [1,25-(OH)₂D₃], or both calcium + 1,25-(OH)₂D₃. In normal mice, 1,25-(OH)₂D₃ treatment was more effective than calcium in turning off 1-hydroxylase and turning on 24-hydroxylase activity; serum calcium, however, was similarly increased by both treatments. Although calcium -I- 1,25-(OH)₂D₃ did not result in a further change in 25OHD₃ metabolism in normal mice, a further elevation in serum calcium was apparent. In Hyp mice, treatment with calcium + 1,25-(OH)₂D₃ resulted in a greater decrease in 1-hydroxylase and a greater increase in 24- hydroxylase and in serum calcium than treatment with either agent alone. In spite of similar serum calcium levels in both genotypes, 24-hydroxylase was 20-fold, 3-fold, and 8-fold greater in Hyp mice relative to normals treated with calcium, 1,25- (OH)₂D₃, and calcium + 1,25-(OH)₂D₃, respectively. Kinetic studies revealed that the maximum velocity (V_max) for induced 24-hydroxylase was 6-fold greater than normal in Hyp mice whereas the apparent Michaelis-Menten constant (K_m) was not different in the two groups of calcium + l,25-(OH)₂D₃-treated mice.

The effect of 1,25-(OH)₂D₃ treatment on the above serum and renal parameters was also examined in vitamin D replete normal and Hyp mice. A sharp rise in serum phosphate was observed in l,25-(OH)₂D₃-treated Hyp mice whereas normal littermates experienced marked hypercalcemia in response to treatment. Renal 24-hydroxylase was significantly stimulated by 1,25-(OH)₂D₃ treatment in both normal and Hyp mice and genotype differences were not apparent.

The present study demonstrates that 1) vitamin D- and calcium-deprived Hyp mice are more responsive to signals which induce 24-hydroxylase than normal littermates; 2) Vma for induced 24-hydroxylase is 6-fold greater in Hyp mice than in normal littermates whereas apparent Km is unchanged; 3) the inhibitory control of 1-hydroxylase appears to be intact in the mutant strain; 4) induced 24-hydroxylase is similar in vitamin D replete normal and Hyp mice; and 5) vitamin D status can thus modify the response of both genotypes to treatment with 1,25-(OH)₂D₃. Clearly, further work will be required to elucidate the mechanism(s) for abnormal regulation of 25OHD₃ metabolism in Hyp mouse kidney. (Endocrinology 120: 609–616,1987)

Footnotes

^* This work was supported by the MRC Genetics Group Grant (to H.S.T.) and by Grant MA-9475 from the Medical Research Council of Canada (to G.J.) and was presented in part at the 6th Workshop on Vitamin D in Merano, Italy, 1985. This is Publication no. 86025 from the McGill University-Montreal Children's Hospital Research Institute.

Received May 28, 1986.

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