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1. Biochem Pharmacol. 2012 May 3. [Epub ahead of print]

Human PXR-mediated induction of intestinal CYP3A4 attenuates
1α,25-dihydroxyvitamin D(3) function in human colon adenocarcinoma LS180 cells.

Zheng XE, Wang Z, Liao MZ, Lin YS, Shuhart MC, Schuetz EG, Thummel KE.

Departments of Pharmaceutics, University of Washington, Seattle, WA.

Oxidative catabolism of 1α,25-dihydroxyvitamin D(3) [1α,25(OH)(2)D(3)] is
mediated by either CYP24A1 or CYP3A4. In this paper, we tested whether induction
of CYP3A4 in the LS180 intestinal cell model enhances clearance of
1α,25(OH)(2)D(3) and blunts its hormonal effect on expression of the apical
membrane calcium transport protein, TRPV6. Treatment with the hPXR agonist
rifampin significantly increased CYP3A4 mRNA content and catalytic activity, but
had no effect on CYP24A1 or TRPV6 mRNA content. Pre-treating cells with rifampin
for 48hrs, prior to a 24hr 1α,25(OH)(2)D(3) treatment phase, was associated with
a subsequent 48% increase in the elimination of 1α,25(OH)(2)D(3) and a 35%
reduction of peak TRPV6 mRNA. Introduction of the CYP3A4 inhibitor,
6',7'-dihydroxybergamottin, an active inhibitor in grapefruit juice, reversed the
effects of rifampin on 1α,25(OH)(2)D(3) clearance and TRPV6 expression.
Over-expression of hPXR in LS180 cells greatly enhanced the CYP3A4 responsiveness
to rifampin pretreatment, and elicited a greater relative suppression of TRPV6
expression and an increase in 1α,25(OH)(2)D(3) disappearance rate, compared to
vector expressed cells, following hormone administration. Together, these results
suggest that induction of CYP3A4 in the intestinal epithelium by hPXR agonists
can result in a greater metabolic clearance of 1α,25(OH)(2)D(3) and reduced
effects of the hormone on the intestinal calcium absorption, which may contribute
to an increased risk of drug-induced osteomalacia/osteoporosis in patients
receiving chronic therapy with potent hPXR agonists. Moreover, ingestion of
grapefruit juice in the at-risk patients could potentially prevent this adverse
drug effect.

Copyright © 2012. Published by Elsevier Inc.

PMID: 22562045 [PubMed - as supplied by publisher]