Dataset Information

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

ABSTRACT: Vitamin D, whose levels vary seasonally with sunlight, is activated to 1?,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, 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.

SUBMITTER: Thirumaran RK

PROVIDER: S-EPMC3774043 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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

Thirumaran Ranjit K RK Lamba Jatinder K JK Kim Richard B RB Urquhart Brad L BL Gregor Jamie C JC Chande Nilesh N Fan Yiping Y Qi An A Cheng Cheng C Thummel Kenneth E KE Hall Stephen D SD Schuetz Erin G EG

Biochemical pharmacology 20120330 1

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/activi ...[more]

PMID: 22484315

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Project description:Domestication and selection of Vitis vinifera L. for table and wine grapes has led to a large level of berry size diversity in current grapevine cultivars. Identifying the genetic basis for this natural variation is paramount both for breeding programs and for elucidating which genes contributed to crop evolution during domestication and selection processes. The gene VvNAC26, which encodes a NAC domain-containing transcription factor, has been related to the early development of grapevine flowers and berries. It was selected as candidate gene for an association study to elucidate its possible participation in the natural variation of reproductive traits in cultivated grapevine.A grapevine collection of 114 varieties was characterized during three consecutive seasons for different berry and bunch traits. The promoter and coding regions of VvNAC26 gene (VIT_01s0026g02710) were sequenced in all the varieties of the collection, and the existing polymorphisms (SNP and INDEL) were detected. The corresponding haplotypes were inferred and used for a phylogenetic analysis. The possible associations between genotypic and phenotypic data were analyzed independently for each season data, using different models and significance thresholds.A total of 30 non-rare polymorphisms were detected in the VvNAC26 sequence, and 26 different haplotypes were inferred. Phylogenetic analysis revealed their clustering in two major haplogroups with marked phenotypic differences in berry size between varieties harboring haplogroup-specific alleles. After correcting the statistical models for the effect of the population genetic stratification, we found a set of polymorphisms associated with berry size explaining between 8.4 and 21.7% (R(2)) of trait variance, including those generating the differentiation between both haplogroups. Haplotypes built from only three polymorphisms (minihaplotypes) were also associated with this trait (R(2): 17.5 - 26.6%), supporting the involvement of this gene in the natural variation for berry size.Our results suggest the participation of VvNAC26 in the determination of the grape berry final size. Different VvNAC26 polymorphisms and their combination showed to be associated with different features of the fruit. The phylogenetic relationships between the VvNAC26 haplotypes and the association results indicate that this nucleotide variation may have contributed to the differentiation between table and wine grapes.

Dataset Information

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

Publications

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

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