Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 170, Issue 1-2, Pages 91-101Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/S0303-7207(00)00330-0
Keywords
25OHD(3); 1 alpha,25(OH)2D(3); 1 alpha,25(OH)(2)-3-epi-D-3; keratinocytes; production; metabolism; 24-hydroxylase
Categories
Funding
- NIDDK NIH HHS [DK-52488] Funding Source: Medline
Ask authors/readers for more resources
Recent studies of metabolism using pharmacological substrate concentrations of 1 alpha ,25-dihydroxyvitamin D-3 [1 alpha ,25(OH)(2)D-3] in several tissues including primary cultures of human keratinocytes, bovine parathyroid cells and bone cells led to the identification of 1 alpha ,25-dihydroxy-3-epi-vitamin D-3 [1 alpha ,25(OH)(2)-3-epi-D-3] as a major natural metabolite of 1 alpha ,25(OH)(2)D-3. In the present study, we demonstrate that human keratinocytes incubated with 25-hydroxy[26,27-H-3] vitamin D-3 produce 1 alpha ,25(OH)(2)-3-epi-D-3 along with 1 alpha ,25(OH)(2)D-3. The production of 1 alpha ,25(OH)(2)-3-epi-D-3 is also identified in human keratinocytes incubated with physiological substrate concentrations of 1 alpha ,25(OH)(2)D-3. Unlike 24-hydroxylase, the major enzyme involved in the further metabolism of 1 alpha ,25(OH)(2)D-3 in human keratinocytes, the enzyme(s) responsible for the production of 1 alpha ,25(OH)(2)-3-epi-D-3 is constitutive and is not inhibited by ketoconazole. It is also noted that 1 alpha ,25(OH)(2)-3-epi-D-3 is further metabolised in human keratinocytes into several as yet unidentified metabolites, the production of which is inhibited to a great extent by SDZ 89-443, an inhibitor of 24-hydroxylase. This finding indicates that the 24-hydroxylase like in the case of 1 alpha ,25(OH)(2)D-3, also plays a major role in the metabolism of 1 alpha ,25(OH)(2)-3-epi-D-3. The results obtained from the metabolism studies performed in parallel among 25OHD(3), 1 alpha ,25(OH)(2)D-3 and 1 alpha ,25(OH)(2)-3-epi-D-3 indicate that 1 alpha ,25(OH)(2)-3-epi-D-3 and its metabolites exhibit higher metabolic stability. In summary, we demonstrate for the first time that 1 alpha ,25(OH)(2)-3-epi-D-3 is a physiological metabolite of 1 alpha ,25(OH)(2)D-3 in human keratinocytes. Also, 1 alpha ,25(OH)(2)-3-epi-D-3 is further metabolised in human keratinocytes mainly through the activity of 24-hydroxylase. Furthermore, our finding of the relative metabolic stability of 1 alpha ,25(OH)(2)-3-epi-D-3 and especially its metabolites when compared to 1 alpha ,25(OH)(2)D-3 and its metabolites provides an important explanation for its previously observed potent inhibitory effect on keratinocyte growth in spite of its low affinity to vitamin D receptor. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available