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1α,25‐Dihydroxy‐3‐Epi‐vitamin D 3 , a natural metabolite of 1α,25‐dihydroxyvitamin D 3 , is a potent suppressor of parathyroid hormone secretion
Author(s) -
Brown A.J.,
Ritter C.,
Slatopolsky E.,
Muralidharan K.R.,
Okamura W.H.,
Reddy G.S.
Publication year - 1999
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/(sici)1097-4644(19990401)73:1<106::aid-jcb12>3.0.co;2-q
Subject(s) - metabolite , parathyroid hormone , chemistry , medicine , endocrinology , calcitriol receptor , vitamin d and neurology , secretion , parathyroid chief cell , calcitriol , stereochemistry , biology , calcium
1α,25(OH) 2 D 3 is an important negative regulator of parathyroid hormone (PTH) gene transcription. In parathyroid cells, as in other target tissues, 1α,25(OH) 2 D 3 is degraded by side chain oxidation by the inducible 24‐hydroxylase. We have previously shown that one metabolite of this pathway, 1α,23(S),25‐(OH) 3 ‐24‐oxo‐D 3 , potently suppresses PTH synthesis and secretion in cultured bovine parathyroid cells (bPTC). Further examination of the metabolites of 1α,25(OH) 2 D 3 in bPTC has revealed another compound that is less polar than 1α,25(OH) 2 D 3 . By HPLC analysis and mass spectrometry, this metabolite was identified as 1α,25(OH) 2 ‐3‐epi‐D 3 . The activity of this metabolite on PTH gene transcription was assessed by the steady‐state PTH secretion by bPTC after 72‐h treatment with concentrations from 10 − 11 M to 10 − 7 M. 1α,25(OH) 2 ‐3‐epi‐D 3 was found to be only slightly, but not significantly, less active than the native 1α,25(OH) 2 D 3 in suppressing PTH secretion despite having 30 times lower affinity for the bPTC VDR. Both 1α,25(OH) 2 D 3 and 1α,25(OH) 2 ‐3‐epi‐D 3 maximally suppressed PTH secretion by 50%. Along with 1α,25(OH) 2 ‐3‐epi‐D 3 , the activities of the other two A‐ring diastereomers were assessed. 1β,25(OH) 2 D 3 suppressed PTH only at 10 − 7 M with a decrease of only 30%, in good agreement with its low VDR affinity. Surprisingly, 1β,25(OH) 2 ‐3‐epi‐D 3 stimulated PTH secretion by 30–50% at concentrations from 10 − 11 M to 10 − 8 M and fell to control (untreated) rates at 10 − 7 M. The mechanism for this increase in PTH secretion is under investigation. Metabolism studies performed in bPTC cells using high concentrations of 1α,25(OH) 2 D 3 substrate showed that in some incubations, the concentration of 1α,25(OH) 2 ‐3‐epi‐D 3 was even higher than that of the parent substrate 1α,25(OH) 2 D 3 . This finding indicates a slower rate of metabolism for this diastereomer. Thus, production and accumulation of 1α,25(OH) 2 ‐3‐epi‐D 3 , as a major stable metabolite of 1α,25(OH) 2 D 3 in parathyroid glands, may contribute to the prolonged suppressive effect of 1α,25(OH) 2 D 3 on PTH gene transcription. J. Cell. Biochem. 73:106–113, 1999. © 1999 Wiley‐Liss, Inc.