A functional C–G polymorphism in the CYP7B1 promoter region and its different distribution in Orientals and Caucasians

Jakobsson, Jenny; Karypidis, Helena; Johansson, J-E; Hk, Roh; Rane, Anders; Ekström, Lena

doi:10.1038/sj.tpj.6500236

Cited by 19 publications

(23 citation statements)

References 25 publications

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“…Promoter mutations that increase transcriptional activity have already been described, for example the UGT1A9*22 allele (Yamanaka et al, 2004) or a C3 G polymorphism in the CYP7B1 promoter (Jakobsson et al, 2004). However, to our knowledge, no TATA box mutations resulting in enhanced transcription or relocation of the transcriptional start site have been described so far.…”

Section: Discussionmentioning

confidence: 90%

A Natural CYP2B6 TATA Box Polymorphism (–82T→ C) Leading to Enhanced Transcription and Relocation of the Transcriptional Start Site

Zukunft¹,

Lang²,

Richter³

et al. 2005

Mol Pharmacol

100

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We investigated the impact of promoter polymorphisms on transcription of the human CYP2B6 gene. In total, 98 DNA samples from white persons from a previously characterized liver bank were sequenced throughout 2.3 kilobases of upstream sequence and haplotype structures were determined using additional coding sequence information. HepG2 cells and primary rat and human hepatocytes were transfected with luciferase reporter gene constructs driven by 2033 base pairs (bp) of the most frequent promoter variants. The novel haplotype *22 (Ϫ1848C3 A, Ϫ801G3 T, Ϫ750T3 C, and Ϫ82T3 C) showed 3-to 9-fold enhanced transcriptional activity in all transfected cells. Constructs containing single mutations surprisingly revealed Ϫ82T3 C, predicted to disrupt a putative TATA box, to be alone responsible for this effect. In silico analysis and electrophoretic mobility shift assay demonstrated conversion of the putative TATA box into a functional CCAAT/ enhancer-binding protein binding site. Analysis of transcriptional start sites showed the mutant promoter to be transcribed from a start site located approximately 30 bp downstream of the wild-type start site, consistent with the use of a noncanonical TATA box at Ϫ55 bp. Median CYP2B6 mRNA expression and bupropion hydroxylase activity as a selective marker of CYP2B6 catalytic activity were approximately 2-fold higher in livers genotyped Ϫ82TC as in those genotyped Ϫ82TT (20.4 versus 9.8 arbitrary units, p ϭ 0.007, and 201.8 versus 106.7 pmol/mg/min, p ϭ 0.042, respectively). This promoter polymorphism thus contributes to CYP2B6 functional variability and represents a novel mechanism by which mutations can enhance transcription. Furthermore, a detailed interspecies comparison of CYP2B promoters and transcriptional start sites provided novel insights into evolutionary relationships.The human cytochrome P450 gene superfamily currently consists of 57 functional genes and 58 pseudogenes (Nelson et al., 2004). The members of families CYP1, CYP2, and CYP3 are localized in the endoplasmic reticulum of both liver and extrahepatic tissues where they catalyze a variety of biotransformations of numerous endogenous and exogenous substrates, including many drugs currently in use. The family member CYP2B6 was first described in 1989 (Yamano et al., 1989) as the human ortholog to the phenobarbital-inducible CYP2B genes in rodents. Initially underestimated, the number of drugs recognized as CYP2B6 substrates has been constantly increasing, and several clinically important substances are now known to be preferred substrates of this enzyme. These include the anticancer prodrug cyclophosphamide (Roy et al., 1999); the narcotic propofol (Court et al., 2001); the antidepressant bupropion, which is now the most commonly used probe drug for CYP2B6 (Faucette et al., 2000); the antimalarial drug artemisinin (Svensson and Ashton, 1999); and the reverse transcriptase inhibitor efavirenz (Ward et al., 2003).

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Section: Discussionmentioning

confidence: 90%

A Natural CYP2B6 TATA Box Polymorphism (–82T→ C) Leading to Enhanced Transcription and Relocation of the Transcriptional Start Site

Zukunft¹,

Lang²,

Richter³

et al. 2005

Mol Pharmacol

100

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“…Prostate cancer is considered to be the most important hormone-related cancers in men [174][175][176][177][178][179]. CYP1A1*2C conferred a higher risk of prostate cancer in Japanese [180,181].…”

Section: Prostate Cancermentioning

confidence: 99%

Cytochrome P450 in Cancer Susceptibility and Treatment

Mittal

Tulsyan

Kumar

et al. 2015

Advances in Clinical Chemistry

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“…The steroid estrogens (E 1 and E 2 ) and the ␤-amyloid peptides ( , and [25][26][27][28][29][30][31][32][33][34][35]) were selected for inhibition studies of the P4507B1-mediated 7␣-hydroxylation of DHEA. Each inhibitor was used at two concentrations, and double reciprocal plots were constructed (Figs.…”

Section: Inhibitions By Estrogens and ␤-Amyloid Peptide Componentsmentioning

confidence: 99%

“…All solvents (Merck, Darmstadt, Germany) were of the reagent grade. The ␤-amyloid peptides ( , , [25][26][27][28][29][30][31][32][33][34][35]) were obtained from Biosource (Nivelles, Belgium) and were dissolved in 0.1% trifluoroacetic acid and diluted for the tests in 0.067 M phosphate buffer (pH 7.4), containing 1 mM EDTA.…”

Section: Introductionmentioning

confidence: 99%