| Aryl hydrocarbon receptor (AhR) ligands and heavy metals are environmental co-contaminants and their molecular interaction may disrupt the coordinated regulation of AhR-dependent phase I and II drug metabolizing enzymes. As such, the effect of the heavy metals, As3+, Cd 2+, and Cr6+, on the AhR-regulated genes: cytochrome P450 1a1 (Cyp1a1), NAD(P)H: quinone oxidoreductase (Nqo1), and glutathione transferase a (Gst a) was investigated in murine hepatoma Hepa 1c1c7 cells. All three metals inhibited the induction of Cyp1a1 activity by AhR ligands while increasing its mRNA expression. On the other hand, As3+ and Cd2+ enhanced Nqo1 and Gst a at the activity and mRNA levels while Cr6+ inhibited their constitutive and inducible expression. Studies investigating the mechanisms involved in the modulation of these AhR-regulated genes revealed a AhR-dependent induction of Cyp1a1 transcription. On the other hand, heavy metals alter Ngo1 expression at the transcriptional level, through a labile protein-mediated pathway. Transcriptional regulation was responsible for the up-regulation of Nqo1 activity by As3+ and Cd2+, whereas post-translational mechanism(s) were involved in the inhibition of Cyp1a1 activity by all three metals. Using the prooxidant buthionine-(S,R)-sulfoximine (BSO) and the antioxidant N-acetylcysteine (NAC), we were able to demonstrate that As3+-, Cd2+-, and Cr6+-induced oxidative stress is responsible for the modulation of Cyp1a1 at the transcriptional and posttranscriptional levels and the induction of Nqo1 and Gst a at the transcriptional level. These results show that the ability of metals to alter the capacity of AhR ligands to induce the bioactivating phase I and the detoxifying phase II enzymes will influence the carcinogenicity and mutagenicity of the AhR ligands. Thus, it comes at no surprise that As 3+ demonstrates anticancer effects. It is likely that the therapeutic efficacy of As3+ is associated with an increase in Ngo1 and Gst a since ascorbic acid potentiates the anticancer effect of As3+ while enhancing the expression of HO-1, Ngo1, and Gst a. Future studies are required to determine the effect of heavy metals on the metabolism of AhR ligands to quantify their effect on the mutagenicity of environmental pollutants and determine the exact role of AhR-regulated genes in the initiation and progression of malignancies. |
