Control of CYP1A2 mRNA levels

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The Pharmacogenomics Journal advance online publication 10 March 2009; doi: 10.1038/tpj.2009.4

Allele-specific expression and gene methylation in the control of CYP1A2 mRNA level in human livers

Roza Ghotbi¹, Alvin Gomez², Lili Milani³, Gunnel Tybring¹, Ann-Christine Syvänen³, Leif Bertilsson¹, Magnus Ingelman-Sundberg² and Eleni Aklillu¹

1. Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
2. Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
3. Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden

Correspondence: Dr E Aklillu, Division of Clinical Pharmacology, Department of Laboratory of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, C-168, SE-141 86 Stockholm, Sweden. E-mail: eleni.aklillu@ki.se

Received 7 October 2008; Revised 13 January 2009; Accepted 3 February 2009; Published online 10 March 2009.

Abstract

The basis for interindividual variation in the CYP1A2 gene expression is not fully understood and the known genetic polymorphisms in the gene provide no explanation. We investigated whether the CYP1A2 gene expression is regulated by DNA methylation and displays allele-specific expression (ASE) using 65 human livers. Forty-eight percent of the livers displayed ASE not associated to the CYP1A2 mRNA levels. The extent of DNA methylation of a CpG island including 17 CpG sites, close to the translation start site, inversely correlated with hepatic CYP1A2 mRNA levels (P=0.018). The methylation of two separate core CpG sites was strongly associated with the CYP1A2 mRNA levels (P=0.005) and ASE phenotype (P=0.01), respectively. The CYP1A2 expression in hepatoma B16A2 cells was strongly induced by treatment with 5-aza-2'-deoxycytidine. In conclusion, the CYP1A2 gene expression is influenced by the extent of DNA methylation and displays ASE, mechanisms contributing to the large interindividual differences in CYP1A2 gene expression.