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

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• 作者：Ranjit K. Thirumaran^a ; ¹ ; ¹² ; ^{Ranjit.thirumaran@stjude.org} ; Jatinder K. Lamba^b ; ² ; ¹² ; ^{lamba004@umn.edu} ; Richard B. Kim^c ; ³ ; ^{Richard.kim@lhsc.on.ca} ; Brad L. Urquhart^d ; ⁴ ; ^{brad.urquhart@schulich.uwo.ca} ; Jamie C. Gregor^e ; ⁵ ; ^{Jamie.gregor@lhsc.on.ca} ; Nilesh Chande^e ; ⁶ ; ^{nilesh.chande@lhsc.on.ca} ; Yiping Fan^f ; ⁷ ; ^{yiping.fan@stjude.org} ; An Qi^g ; ⁸ ; ^{qi.an@stjude.org} ; Cheng Cheng^g ; ⁹ ; ^{cheng.cheng@stjude.org} ; Kenneth E. Thummel^h ; ¹⁰ ; ^{thummel@u.washington.edu} ; Stephen D. Hallⁱ ; ¹¹ ; ^{hallst@lilly.com} ; Erin G. Schuetz^a ; ^{erin.schuetz@stjude.org}
• 关键词：CYP3A4 ; Vitamin D ; VDR ; Polymorphism ; Seasonal variation
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：1 July, 2012
• 卷：84
• 期：1
• 页码：104-112
• 文件大小：477 K

摘要

Vitamin D, whose levels vary seasonally with sunlight, is activated to 1伪,25-dihydroxyvitamin D₃ 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, with CYP3A4 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.