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1. Biochem Pharmacol. 2012 Mar 30. [Epub ahead of print]

Intestinal CYP3A4 and midazolam disposition in vivo associate with VDR
polymorphisms and show seasonal variation.

Thirumaran RK, Lamba JK, Kim RB, Urquhart BL, Gregor JC, Chande N, Fan Y, Qi A,
Cheng C, Thummel KE, Hall SD, Schuetz EG.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital,
Memphis, TN, United States.

Vitamin D, whose levels vary seasonally with sunlight, is activated to
1α,25-dihydroxyvitamin D(3) that binds the vitamin D receptor (VDR) and
transcriptionally regulates intestinal CYP3A4 expression. We genotyped VDR
polymorphisms and determined their associations with intestinal CYP3A4 and with
midazolam pharmacokinetics, and whether intestinal CYP3A4 levels/activity varied
seasonally. The VDR BsmIG>A (rs1544410) polymorphism was significantly associated
with CYP3A4 jejunal expression/activity, withCYP3A4 duodenal mRNA, and with
midazolam area under the curve (AUC). Intestinal CYP3A4 expression/activity was
significantly higher in biopsies with the VDR promoter polymorphisms Cdx2-3731G>A
and GATA-1012A>G that increase VDR activation of target genes. Duodenal CYP3A4
mRNA was significantly higher between April and September than between October
and March. Midazolam p.o. AUC and oral bioavailability trended higher October
through March compared to April through September. These data suggest VDR
polymorphisms are predictors of intestinal CYP3A4, and that CYP3A4 intestinal
expression varies seasonally - likely related to annual changes in UV sunlight
and vitamin D levels.

Copyright © 2012. Published by Elsevier Inc.

PMID: 22484315 [PubMed - as supplied by publisher]