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First published on February 18, 2005; DOI: 10.1124/mol.104.008086

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Received for publication October 12, 2004.
Revised January 31, 2005.
Accepted for publication February 18, 2005.

A natural CYP2B6 TATA box-polymorphism (-82T>C) leading to enhanced transcription and relocation of the transcriptional start site

Joerg Zukunft 1, Thomas Lang 2, Tanja Richter 1, Karen I Hirsch-Ernst 3, Andreas K Nussler 4, Kathrin Klein 1, Matthias Schwab 1, Michel Eichelbaum 1, Ulrich M. Zanger 5*

1 Dr.Margarete Fischer-Bosch Institute of Clinical Pharmacology 2 EPIDAUROS AG, Bernried, Germany 3 Department of Toxicology, Goettingen, Germany 4 Department of Surgery, Charite, Berlin, Germany 5 Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

* Address correspondence to: E-mail: uli.zanger{at}ikp-stuttgart.de

Abstract

We investigated the impact of promoter polymorphisms on transcription of the human CYP2B6 gene. A total of 98 Caucasian DNA samples from a previously characterized liver bank were sequenced throughout 2.3 kb 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 bp of the most frequent promoter variants. The novel haplotype *22 (-1848C>A, -801G>T, -750T>C and -82T>C) showed three- to ninefold enhanced transcriptional activity in all transfected cells. Constructs containing single mutations surprisingly revealed -82T>C, predicted to disrupt a putative TATA box, to be alone responsible for this effect. In silico analysis and electrophoretic mobility shift assay suggested conversion of the putative TATA box into a functional C/EBP binding site. Analysis of transcriptional start sites showed the mutant promoter to be transcribed from a start site located about 30 bp downstream of the wild type start site, consistent with the use of a noncanonical TATA box at -55 bp. Median CYP2B6 mRNA expression and bupropion hydroxylase activity as a selective marker of CYP2B6 catalytic activity were about twofold higher in livers genotyped -82TC as in those genotyped -82TT (20.4 vs. 9.8 a.u., p=0.007, and 201.8 vs. 106.7 pmol/mg*min, p=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 inter-species comparison of CYP2B promoters and transcription start sites provided novel insights into evolutionary relationships.


Key words: Promoter analysis, Cytochrome P450, Genetics, Regulation - transcriptional


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