ABSTRACT
Vitamin D is a secosteroid derived from cholesterol by opening of the B ring. A series of mitochondrial P450 enzymes bio-activate vitamin D to 1,25(OH)2D, which then functions as a classical steroid hormone by binding to a nuclear, zinc-finger receptor. The 25hydroxylation of vitamin D to 25-hydroxylation vitamin D (25OHD) in the liver is rapid and not regulated, so that 25OHD is the most abundant metabolite in blood, at 107 M. Renal 1αhydroxylation of 25OHD to 1,25 dihydroxyvitamin D (1,25(OH)2D) is rate-limiting and highly regulated, so that most physiologic and genetic attention has been directed to the 1αhydroxylase. After decades of effort, four groups succeeded in cloning this enzyme, P450c1α (also known as CYP27B), in late 1997. Mutations in P450c1α cause vitamin Ddependent rickets type I, a rare and severe disorder of calcium metabolism which can be treated successfully with oral replacement of 1α-hydroxylated metabolites of vitamin D. The cloning of the gene for P450c1α should rapidly advance knowledge of the physiologic regulation of its transcription.
