1,25-Dihydroxyvitamin D is not responsible for toxicity caused by vitamin D or 25-hydroxyvitamin D.
Vitamin D intoxication was produced with oral doses of either vitamin D₃ or 25-hydroxyvitamin D₃ in CYP27B1 -/- (1α-hydroxylase knockout) and wild-type mice. These compounds were equally toxic in wild-type and the mutant mice. Since the null mutant mice are unable to produce 1,25-dihydroxyvitamin D, it is clear 1,25-dihydroxyvitamin D is not responsible for vitamin D intoxication. On the other hand, 25-hydroxyvitamin D rises to levels of 400-700 ng/ml or 1000-1750 nM in the serum of both groups of mice. Toxicity was evidenced by severe hypercalcemia and weight loss. Measurement of 1,25-dihydroxyvitamin D₃ in serum confirmed its absence from serum of the CYP27B1 -/- mice given 25-hydroxyvitamin D₃. Since high concentrations of 25-hydroxyvitamin D can bind the vitamin D receptor and can induce transcription, 25-hydroxyvitamin D is likely responsible for toxicity of vitamin D excess.
Department of Biochemistry, University of Wisconsin-Madison, United States. deluca@biochem.wisc.eud
Hector F
HF
Deluca
Jean M
JM
Prahl
Lori A
LA
Plum
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002112:Calcifediol / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D002117:Calcitriol / Q000097:blood / Q000378:metabolism / Q000633:toxicity; D055786:Gene Knockout Techniques; D008297:Male; D051379:Mice; D014158:Transcription, Genetic / Q000187:drug effects; D014807:Vitamin D / Q000097:blood / Q000378:metabolism / Q000633:toxicity*
D014807:Vitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002112:Calcifediol