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• W2007788206 startingPage "113" @default.
• W2007788206 abstract "Co-contamination with complex mixtures of heavy metals, such as lead (Pb2+) 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 Pb2+ 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 Pb2+ 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 Pb2+ induced NAD(P)H:Quinone oxidoreductase 1 mRNA. Mechanistically, the Pb2+-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 Pb2+ 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 Pb2+-mediated inhibition of CYP1A1 induction by TCDD. In addition, transfection of HepG2 cells with siRNA targeting the human HO-1 gene restored the Pb2+-mediated inhibition of TCDD-induced CYP1A1. In conclusion, this study demonstrated that Pb2+ down-regulates the expression of CYP1A1 through transcriptional and posttranslational mechanisms and confirms the role of HO-1 in a Pb2+-mediated effect." @default.
• W2007788206 created "2016-06-24" @default.
• W2007788206 creator A5053384151 @default.
• W2007788206 creator A5085002944 @default.
• W2007788206 date "2012-01-01" @default.
• W2007788206 modified "2023-10-03" @default.
• W2007788206 title "Transcriptional and posttranslational mechanisms modulating the expression of the cytochrome P450 1A1 gene by lead in HepG2 cells: A role of heme oxygenase" @default.
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• W2007788206 doi "https://doi.org/10.1016/j.tox.2011.11.006" @default.
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