The mechanism of 1,25-dihydroxyvitamin D(3) autoregulation in keratinocytes.
The synthesis of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) from its precursor, 25-dihydroxyvitamin D(3) (25(OH)D(3)), is catalyzed by the mitochondrial cytochrome P450 enzyme 25-hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-hydroxylase). It has been generally assumed that 1,25(OH)(2)D(3) inhibits the activity of this enzyme by regulating its expression at the genomic level. We confirmed that 1,25(OH)(2)D(3) reduced the apparent conversion of 25(OH)D(3) to 1,25(OH)(2)D(3) while stimulating the conversion of 1,25(OH)(2)D(3) and 25(OH)D(3) to 1,24,25(OH)(3)D(3) and 24,25(OH)(2)D(3), respectively. However, 1,25(OH)(2)D(3) failed to reduce the abundance of its mRNA or its encoded protein in human keratinocytes. Instead, when catabolism of 1,25(OH)(2)D(3) was blocked with a specific inhibitor of the 25-hydroxyvitamin D(3)-24-hydroxylase (24-hydroxylase) all apparent inhibition of 1alpha-hydroxylase activity by 1,25(OH)(2)D(3) was reversed. Thus, the apparent reduction in 1alpha-hydroxylase activity induced by 1,25(OH)(2)D(3) is due to increased catabolism of both substrate and product by the 24-hydroxylase. We believe this to be a unique mechanism for autoregulation of steroid hormone synthesis.
Xie
Zhongjian
Z
Endocrine Unit, Veterans Affairs Medical Center, University of California, San Francisco, California 94121, USA. zjxie@itsa.ucsf.edu
Munson
Scott J
SJ
Huang
Ningwu
N
Portale
Anthony A
AA
Miller
Walter L
WL
Bikle
Daniel D
DD
D002117:Calcitriol / Q000502:physiology*; D002478:Cells, Cultured; D053493:Cholestanetriol 26-Monooxygenase; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006706:Homeostasis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007231:Infant, Newborn; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D007700:Kinetics; D008297:Male; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D065668:Vitamin D3 24-Hydroxylase
D004791:Enzyme Inhibitors; D007093:Imidazoles; C429906:VID 400; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol