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Environmental toxicology and pharmacology

The effect of aryl hydrocarbon receptor ligands on the expression of polymerase (DNA directed) kappa (Polκ), polymerase RNA II (DNA directed) polypeptide A (PolR2a), CYP1B1 and CYP1A1 genes in rat liver.


PMID 23026235

Abstract

The aryl hydrocarbon receptor (AhR) mediates a variety of biological responses to ubiquitous environmental pollutants. AhR is ligand activated transcription factor with high affinities for aromatic planar compounds such as β-naphthoflavone (BNF), 3-methylcholanthrene (3-MC), benzo[a]pyrene (BaP) or dioxin (TCDD). After binding appropriate ligand, AhR trigger induction of expression of some phase I and phase II drug metabolizing genes together with numerous other genes. One of such gene appear to be polymerase (DNA directed) kappa (Polκ). Polκ gene encodes newly identified low fidelity DNA polymerase. The enzyme bypasses benzo[a]pyrene-N2-dG lesions in a mostly error free manner by incorporating predominantly dC opposite the bulky lesions. It was demonstrated that AhR activation increases expression of the mouse Polκ gene and probably human POLK gene. In this study we examined the effect of i.p. administration of different AhR ligands on the expression of Polκ, RNA polymerase II polypeptide A (PolR2a) and cytochrome P450 1B1 (CYP1B1), the genes controlled by AhR in Sprague-Dawley rat liver. Quantitative real-time RT-PCR analysis revealed significant induction in the mRNA expression levels of Polκ and PolR2a following BNF treatment. Time courses of mRNA expression after treatment with BNF were similar in both genes, with maximal increases at 8h after treatment. The maximal induction of CYP1B1 and CYP1A1 expression was observed after 24 and 8h after BNF injection, respectively. TCDD treatment caused the significant increase in the mRNA level of CYP1B1 at 72h after administration of the ligand but no effect on Polκ and PolR2a mRNA expression was observed. These results confirm connection between AhR and Polκ, and strongly suggest that AhR up-regulates the mRNA transcription of PolR2a as well. However physiological importance of AhR dependent regulation of PolR2a expression must be further elucidated.