Ascorbic acid differentially modulates the induction of heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1 and glutathione S-transferase Ya by As3+, Cd2+ and Cr6+

The induction of phase II drug metabolizing enzymes serves as a detoxification mechanism for many mutagens, carcinogens and other toxic compounds. Specifically, NAD(P)H:quinone oxidoreductase 1 (Nqo1) and glutathione S-transferase Ya subunit (Gst ya) are key enzymes involved in cellular defense against reactive forms of oxygen and the inhibition of carcinogenesis. As3+, which induces these enzymes, has been proven to have a role in the treatment of acute promyelocytic leukemia. Ascorbic acid (AA) potentiates the anticancer effect of As3+ and thus it is expected that this antioxidant will have a paradoxical effect on the ability of heavy metals, specifically As3+, to induce Nqo1 and Gst ya. We have shown that As3+ and Cd2+ induce heme oxygenase-1 (HO-1), Nqo1 and Gst ya mRNA levels but Cr6+ decreases Nqo1 and Gst ya mRNA. Surprisingly, AA superinduced the induction of HO-1, Nqo1 and Gst ya mRNA by As3+, while inhibiting the induction of HO-1 mRNA by Cd2+ and Cr6+. Hence, it is tempting to speculate that AA may potentiate the therapeutic efficacy of As3+ by enhancing the expression of HO-1, Nqo1, and Gst ya while acting as a potent antioxidant.