title: Modulation of carcinogen metabolism by nitric oxide-aspirin 2 is associated with suppression of DNA damage and DNA adduct formation.
abstract: Nitric oxide (NO)-donating non-steroidal anti-inflammatory drugs (NSAIDs) represent a promising new class of drugs developed to provide a safer alternative than their conventional NSAID counterparts in chemoprevention. We tested the effects of NO-aspirin 2 on Phase I and Phase II carcinogen-metabolizing enzymes. In HepG2 human hepatoma cells and in LS180 colonic adenocarcinoma cells, NO-aspirin 2 inhibited 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD)-induced cytochrome P450 (CYP) enzyme activity and CYP1A1 and CYP1A2 mRNA expression. These effects were further characterized as being mediated through transcriptional regulation: NO-aspirin 2 inhibited binding of ligand (TCDD)-activated aryl hydrocarbon receptor to the CYP1A1 enhancer sequence; additionally, NO-aspirin 2 suppressed carcinogen-induced expression of CYP1A heterogeneous nuclear RNA. The fate of carcinogen metabolites depends not only on activation by CYP enzymes but also detoxification by Phase II enzymes. Both HepG2 and LS180 cells treated with NO-aspirin 2 showed an increase in glutathione S-transferase-P1 (GST-P1), glutamate-cysteine ligase (GCL), and NAD(P)H:quinone oxidoreductase-1 (NQO1) expression. Compared with two other NO-releasing compounds, diethylenetriamine-NO and the organic nitrate, isosorbide dinitrate, the inhibitory effects of NO-aspirin 2 on TCDD-induced CYP activity and mRNA expression were considerably more potent. Furthermore, aspirin alone had no inhibitory effect on TCDD-induced CYP activity, nor did aspirin up-regulate GCL, GST-P1, or NQO1 expression. Consequent to the effects on carcinogen-metabolizing enzymes, NO-aspirin 2 inhibited [3H]benzo[a]pyrene-DNA adduct formation and DNA damage elicited by TCDD or benzo[a]pyrene. Our results demonstrate that NO-aspirin 2 may be an effective chemopreventive agent by favorably affecting the inhibitory and enhancing effects of Phase I and Phase II carcinogen metabolism, thereby protecting DNA from carcinogenic insult.
authors: Cellular Defense and Carcinogenesis Section, Laboratory of Metabolism.
authors: Christopher J
authors: CJ
authors: MacDonald
authors: Cellular Defense and Carcinogenesis Section, Laboratory of Metabolism.
authors: Robert Y S
authors: RYS
authors: Cheng
authors: Laboratory of Pathology, Frederick, Maryland 21702.
authors: David D
authors: DD
authors: Roberts
authors: Radiation Biology Branch, Center for Cancer Research, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702.
authors: David A
authors: DA
authors: Wink
authors: Cellular Defense and Carcinogenesis Section, Laboratory of Metabolism.
authors: Grace Chao
authors: GC
authors: Yeh
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001241:Aspirin / Q000737:chemistry*; D002273:Carcinogens / Q000737:chemistry*; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D009569:Nitric Oxide / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry; D000072317:Polychlorinated Dibenzodioxins / Q000737:chemistry; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011994:Recombinant Proteins; D009569:Nitric Oxide; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D001241:Aspirin; D010100:Oxygen