INORGANIC COMPOUNDS Differential modulation of aryl hydrocarbon receptor regulated enzymes by arsenite in the kidney, lung, and heart of C57BL/6 mice Anwar Anwar-Mohamed • Ghada Abdelhamid • Issa E. A. Amara • Ayman O. S. El-Kadi Received: 21 February 2012 / Accepted: 10 April 2012 / Published online: 26 April 2012 Ó Springer-Verlag 2012 Abstract During the last couple of decades, efforts have been made to study the toxic effects of individual aryl hydrocarbon receptors (AhR) ligands such as 2,3,7,8-tetra- chlorodibenzo-p-dioxin (TCDD) or heavy metals typified by arsenic As(III). However, little is known about the combined toxic effects of TCDD and As(III) in vivo. Previous reports from our laboratory and others have demonstrated that As(III), by itself or in the presence of AhR ligands, such as TCDD, is capable of differentially altering the expression of various phase I and phase II AhR-regulated genes in in vitro systems. Thus, the objective of the current study was to investigate whether or not similar effects would occur at the in vivo level. Therefore, we examined the effect of exposure to As(III) (12.5 mg/kg) in the absence and presence of TCDD (15 lg/kg) on the AhR-regulated genes using C57Bl/ 6 mice. Our results demonstrated that As(III) alone inhibited Cyp1a1 and Cyp1a2 in the kidney, while it induced their levels in the lung and did not affect their mRNA levels in the heart. As(III) also induced Nqo1 and Gsta1 in all tested tis- sues. Upon co-exposure to As(III) and TCDD, As(III) inhibited the TCDD-mediated induction of Cyp1a1 in the kidney and heart, Cyp1a2 in the kidney and heart, while it potentiated TCDD-mediated induction of Cyp1a1 in the lung, and Nqo1 and Gsta1 in the kidney and lung. In con- clusion, the present study demonstrates for the first time that As(III) modulates constitutive and TCDD-induced AhR- regulated genes in a time-, tissue-, and AhR-regulated enzyme-specific manner. Keywords AhR Á Arsenite Á Cyp1a1 Á Cyp1a2 Á Nqo1 Á Gsta1 Abbreviations AhR Aryl hydrocarbon receptor As(III) Arsenite Cyp450s Cytochrome P450s Gsta1 Glutathione-S-transferase A1 HO-1 Heme oxygenase-1 Nqo1 NADP(H): quinone oxidoreductase TCDD 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) XRE Xenobiotic responsive element Introduction The AhR is a member of basic-helix-loop-helix (bHLH)/ Per-ARNT-Sim (PAS) family of transcription proteins. Inactive AhR resides in the cytoplasm bound to two 90-kDa heat shock proteins (HSP90), the 23-kDa heat shock protein (p23), and hepatitis B virus X-associated protein 2 (XAP2). Upon ligand binding, the AhR–ligand complex dissociates from the cytoplasmic complex and translocates to the nucleus where it associates with the aryl hydrocarbon receptor nuclear translocator (ARNT) (Nebert and Duffy 1997). The whole complex then acts as a tran- scription factor that binds to a specific DNA recognition sequence, termed the xenobiotic responsive element (XRE), located in the promoter region of a number of AhR- regulated genes. Among these genes are those encoding a number of xenobiotic metabolizing enzymes, including four phase I enzymes [cytochrome P450 1A1 (CYP1A1), CYP1A2, CYP1B1, and CYP2S1] and four phase II enzymes [NAD(P)H: quinone oxidoreductase-1 (NQO1), A. Anwar-Mohamed Á G. Abdelhamid Á I. E. A. Amara Á A. O. S. El-Kadi (&) Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB T6G 2N8, Canada e-mail: aelkadi@pharmacy.ualberta.ca 123 Arch Toxicol (2012) 86:897–910 DOI 10.1007/s00204-012-0855-x