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 Issa E.A. Amara, Anwar Anwar-Mohamed, Ayman O.S. El-Kadi∗ 

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8 


a r t i c l e i n f o 

Keywords: CYP1A1 Mercury Dioxin Heavy metals Toxicity 

a b s t r a c t 

Aryl hydrocarbon receptor (AhR) ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and metals, such as mercury (Hg2+), are environmental co-contaminants and their molecular interaction may disrupt the coordinated regulation of the carcinogen-activating enzyme cytochrome P450 1A1 (CYP1A1). There- fore, we examined the effect of co-exposure to Hg2+ and TCDD on the expression of the CYP1A1 in HepG2 cells. Our results showed that Hg2+ significantly inhibited the TCDD-mediated induction of CYP1A1 at the mRNA, protein, and catalytic activity levels. At the transcriptional level, co-exposure to Hg2+ and TCDD significantly decreased the TCDD-mediated induction of AhR-dependent luciferase reporter gene expression. Moreover, Hg2+ did not affect CYP1A1 mRNA stability, while decreasing its protein half-life, suggesting the involvement of a posttranslational mechanism. Importantly, Hg2+ increased the expres- sion of heme oxygenase-1 (HO-1), a rate limiting enzyme in heme degradation, which coincided with further decrease in the CYP1A1 catalytic activity levels. Upon using a competitive HO-1 inhibitor, tin mesoporphyrin, heme precursor, hemin, or transfecting the HepG2 cells with siRNA for HO-1 there was a partial restoration of the inhibition of TCDD-mediated induction of CYP1A1 catalytic activity. In con- clusion, we demonstrate that Hg2+ down-regulates the expression of CYP1A1 at the transcriptional and posttranslational levels in HepG2 cells. In addition, HO-1 is involved in the modulation of CYP1A1 at the posttranslational level. 

© 2010 Elsevier Ireland Ltd. All rights reserved. 

1. Introduction 

Co-contamination of heavy metals, such as mercury (Hg2+), with halogenated aromatic hydrocarbons (HAHs) such as 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD), is a common environmental problem with multiple biological consequences. Hg2+ is mostly considered highly toxic agent that is introduced into the environ- ment through natural and/or industrial sources (Snow et al., 1989). Both aryl hydrocarbon receptor (AhR) ligands and heavy metals are ranked high on the list of the most hazardous xenobiotics in the environment, as reported by the Agency for Toxic Substances and Diseases Registry and the Canadian Environmental Protection Act. (ATSDR, 2005; CEPA, 2006). Studies on the carcinogenicity and mutagenicity of HAHs have demonstrated the role of cytochrome P450 1A1 (CYP1A1), a phase I xenobiotics-metabolizing enzyme, in bioactivating poly aromatic hydrocarbons (PAHs) to epoxide and diol-epoxide intermediates, which will subsequently lead to 

∗ Corresponding author at: Faculty of Pharmacy & Pharmaceutical Sciences, 3126 Dentistry/Pharmacy Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2N8. Tel.: +1 780 492 3071; fax: +1 780 492 1217. 

E-mail address: aelkadi@pharmacy.ualberta.ca (A.O.S. El-Kadi). 

DNA and protein adducts formation (Shimada and Fujii-Kuriyama, 2004). 

The AhR is a ligand-activated cytoplasmic transcription fac- tor that belongs to the basic-helix-loop-helix protein family. The AhR plays a key role in the regulation of CYP1A1. This cytosolic inactive receptor exists attached to a complex of two heat shock proteins 90 (HSP90), hepatitis B virus X-associated protein (XAP2), and the chaperone protein p23 (Hankinson, 1995; Meyer et al., 1998). Upon ligand binding, the activated AhR dissociates from the cytoplasmic complex, and translocates to the nucleus where it dimerizes with the aryl hydrocarbon nuclear translocator (Arnt) (Whitelaw et al., 1994). Thereafter, the ligand/AhR/Arnt complex acts as a transcription factor that binds to a specific DNA recogni- tion sequence, GCGTG, within the xenobiotic responsive element (XRE), located in the promoter region of a battery of genes termed AhR-regulated genes such as CYP1A1 (Denison et al., 1989; Nebert et al., 2004). The toxicological effects of HAHs, typified by TCDD, are mainly mediated through the activation of AhR and conse- quently CYP1A1. In fact, a strong correlation between the induction of CYP1A1 and cancer has been previously reported (McLemore et al., 1990). 

The majority of published studies on AhR ligands toxicities have been conducted individually, yet human exposures are usually to 
0378-4274/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.toxlet.2010.09.003 
journal homepage: www.elsevier.com/locate/toxlet 
Toxicology Letters 199 (2010) 225–233 
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