The contribution of n-oxidation to the metabolism of the food-borne carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in rat hepatocytes

Robert J. Turesky, Ingrid Bracco-Hammer, Jovanka Markovic, Urs Richli, Anne Marie Kappeler, Dieter H. Welti

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56 Scopus citations


The metabolism of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, a potent bacterial mutagen and rodent carcinogen formed in low quantities in cooked meat and fish, was studied in freshly isolated rat hepatocytes. Ten metabolites were characterized by various spectroscopic methods. Sulfamate formation was the major route of metabolism in hepatocytes of untreated rats whereas ring-hydroxylated sulfuric and glucuronic acid conjugates were major metabolites in animals pretreated with the enzyme inducers Aroclor-1254, β-naphthoflavone, or isosafrole. The formation of a mutagenic metabolite through N-oxidation, 2-(hydroxyamino)-3,8-dimethylimidazo[4,5- f]quinoxaline (HNOH-MeIQx), was an important route of metabolism in hepatocytes of pretreated animals. Its metastable derivative, the N-hydroxy-N-glucuronide, also was detected. The nitro derivative of MeIQx, a direct-acting bacterial mutagen, was readily detoxified by glutathione transferase, forming a conjugate where the thiol group of glutathione displaced the nitro moiety. Low but detectable levels of N-acetyltransferase activity were observed for MelQx and sulfamethazine in hepatocytes. HNOH-MeIQx and 4-(hydroxyamino)biphenyl (HNOH-ABP), a recognized human carcinogen, displayed acetyl coenzyme A dependent DNA binding in hepatic cytosol assays. Sulfamethazine decreased the DNA binding of HNOH-MeIQx in hepatocytes, suggesting a competition for acetyltransferase. However, the binding of HNOH-MelQx to DNA in hepatocytes was independent of sulfotransferase since inhibitors of this enzyme, 2,6-dichloro-4-nitrophenol (DCNP) and pentachlorophenol (PCP), did not diminish DNA binding. In contrast, binding of HNOH-ABP to DNA was not decreased by sulfamethazine, but binding was diminished by both sulfotransferase inhibitors. From these inhibition experiments it appears that a major route of binding of -MeIQx to DNA in hepatocytes is mediated through O-acetyltransferase while a significant portion of HNOH-ABP bound to DNA is catalyzed by sulfotransferase.

Original languageEnglish (US)
Pages (from-to)524-535
Number of pages12
JournalChemical research in toxicology
Issue number6
StatePublished - 1990


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