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

Abstract

Vitamin D, whose levels vary seasonally with UV sunlight, binds the vitamin D receptor (VDR) and transcriptionally regulates intestinal CYP3A4 expression. We tested the hypothesis that intestinal CYP3A4 expression and midazolam disposition in vivo varies seasonally and is associated with VDR genotype. We genotyped six polymorphisms in the VDR gene and determined their associations with CYP3A4 intestinal expression and activity. Significant associations were observed between the VDR polymorphism in intron 8 rs1544410 (BsmIG>A) and (a) CYP3A4 jejunal protein expression and activity, (b) CYP3A4 duodenal mRNA expression, and (c) midazolam dose adjusted AUC. Intestinal CYP3A4 expression/activity was significantly higher in biopsies with the VDR promoter polymorphisms rs11568820 (Cdx2-3731G>A) and rs4516035 (GATA-1012A>G) that are known to increase binding of Cdx2 and GATA and increase VDR transcriptional activation of target genes. Duodenum CYP3A4 mRNA levels was significantly higher between April and September than between October and March. Dose-adjusted midazolam p.o. AUC and bioavailability were each higher (and weight adjusted midazolam oral clearance was lower) in October-March compared to April through September. We conclude that these data provide support for VDR polymorphisms as predictors of intestinal CYP3A4 expression, and that intestinal CYP3A4 expression and midazolam dose-adjusted AUC and bioavailability show seasonal variation that is likely related to annual changes in UV sunlight and vitamin D levels. This is the first example of a gene (VDR) / environment (seasonal variation in UV sunlight and presumably Vitamin D) interaction regulating intestinal CYP3A4. IMPORTANCE OF THIS STUDY CYP3A represent the largest piece of the intestinal CYPP450 pie 1, 25-(OH)2vitamin D3 induces CYP3A4 in Caco-2 Distribution of CYP3A4 & villin in the human small intestine Comparison of relative VDR mRNA content in liver & small intestinal mucosa As VDR is predominantly expressed in intestine it could influence the intestinal expression CYP3A4 that would result in increased metabolism of CYP3A4 drug substrates Rational for VDR SNP Selection VDR is an important regulator of intestinal CYP3A4 expression RESULTS