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Toxicology. 2012 Jan 27;291(1-3):113-21. doi: 10.1016/j.tox.2011.11.006. Epub 2011 Nov 22.

Transcriptional and posttranslational mechanisms modulating the expression of the cytochrome P450 1A1 gene by lead in HepG2 cells: a role of heme oxygenase.

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  • 1Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.

Abstract

Co-contamination with complex mixtures of heavy metals, such as lead (Pb(2+)) and halogenated aromatic hydrocarbons (HAHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may disrupt the coordinated regulation of the carcinogen activating enzyme cytochrome P450 1A1 (CYP1A1). Therefore, in this study we examined the effects of co-exposure to Pb(2+) and TCDD on the expression of CYP1A1 in human hepatoma HepG2 cells and explored the involvement of transcriptional and posttranscriptional mechanisms. Our results showed that Pb(2+) significantly decreased TCDD-induced CYP1A1 mRNA, protein, and catalytic activity levels in a concentration-dependent manner. Importantly, this inhibition is specific to CYP1A1 and not to other aryl hydrocarbon receptor (AhR)-regulated gene, as Pb(2+) induced NAD(P)H:Quinone oxidoreductase 1 mRNA. Mechanistically, the Pb(2+)-mediated inhibition of CYP1A1 was associated with a significant decrease in the xenobiotic responsive element (XRE)-dependent luciferase activity without affecting the level of AhR protein, suggesting a transcriptional mechanism. On the other hand, the inhibitory effect of Pb(2+) on the induction of CYP1A1 coincided with an increase in heme oxygenase-1 (HO-1) mRNA level and reactive oxygen species production at the posttranslational level. Furthermore, the inhibition of HO-1 activity, by tin mesoporphyrin, or supplementing heme, using hemin, caused a partial restoration of Pb(2+)-mediated inhibition of CYP1A1 induction by TCDD. In addition, transfection of HepG2 cells with siRNA targeting the human HO-1 gene restored the Pb(2+)-mediated inhibition of TCDD-induced CYP1A1. In conclusion, this study demonstrated that Pb(2+) down-regulates the expression of CYP1A1 through transcriptional and posttranslational mechanisms and confirms the role of HO-1 in a Pb(2+)-mediated effect.

PMID:
22120038
DOI:
10.1016/j.tox.2011.11.006
[PubMed - indexed for MEDLINE]
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