Ascorbic acid differentially modulates the induction of heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1 and glutathione S-transferase Ya by As(3+), Cd(2+) and Cr(6+).
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. As(3+), 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 As(3+) and thus it is expected that this antioxidant will have a paradoxical effect on the ability of heavy metals, specifically As(3+), to induce Nqo1 and Gst ya. We have shown that As(3+) and Cd(2+) induce heme oxygenase-1 (HO-1), Nqo1 and Gst ya mRNA levels but Cr(6+) decreases Nqo1 and Gst ya mRNA. Surprisingly, AA superinduced the induction of HO-1, Nqo1 and Gst ya mRNA by As(3+), while inhibiting the induction of HO-1 mRNA by Cd(2+) and Cr(6+). Hence, it is tempting to speculate that AA may potentiate the therapeutic efficacy of As(3+) by enhancing the expression of HO-1, Nqo1, and Gst ya while acting as a potent antioxidant.
Elbekai
Reem H
RH
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta, Canada.
Duke
John
J
El-Kadi
Ayman O S
AO
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001152:Arsenicals / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D015152:Blotting, Northern; D019187:Cadmium Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D017608:Chromium Compounds / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics*; D051547:Heme Oxygenase-1 / Q000235:genetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D009942:Organometallic Compounds / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D001152:Arsenicals; D019187:Cadmium Compounds; D017608:Chromium Compounds; D009942:Organometallic Compounds; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D019363:Cytochrome P-450 CYP1A1; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D005982:Glutathione Transferase; D001205:Ascorbic Acid