Bioactivation of 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843) to reactive intermediates that bind covalently to macromolecules and produce genotoxicity
| Autor: | Z, Zhao, K A, Koeplinger, G E, Padbury, M J, Hauer, G L, Bundy, L S, Banitt, T M, Schwartz, D C, Zimmermann, P R, Harbach, J K, Mayo, C S, Aaron |
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| Rok vydání: | 1996 |
| Předmět: |
Male
DNA Repair Free Radical Scavengers Haplorhini In Vitro Techniques Spectrometry Mass Fast Atom Bombardment Gas Chromatography-Mass Spectrometry Rats Inbred F344 Rats Dogs Pyrimidines Microsomes Liver Animals Humans Pyrroles Spectrophotometry Ultraviolet Biotransformation Chromatography High Pressure Liquid Mutagens Protein Binding |
| Zdroj: | Chemical research in toxicology. 9(8) |
| ISSN: | 0893-228X |
| Popis: | U-89843 is a novel pyrrolo[2,3-d]pyrimidine antioxidant with prophylactic activity in animal models of lung inflammation. During preclinical safety evaluation, U-89843 was found to give a positive response in the in vitro unscheduled DNA synthesis (UDS) assay, an assay which measures DNA repair following chemically-induced DNA damage in metabolically competent rat hepatocytes. Incubation of [14C]U-89843 with liver microsomes resulted in covalent binding of radioactive material to macromolecules by a process that was NADPH-dependent. U-89843 has been shown to undergo C-6 methylhydroxylation to give U-97924, in rat both in vivo and in vitro, in a reaction catalyzed by cytochrome P450 2C11. Synthetical U-97924 is chemically reactive and undergoes dimerization in aqueous solution. The dimerization of U-97924 was significantly inhibited by addition of nucleophiles such as methanol, glutathione, and N-acetylcysteine. Characterization of the corresponding methanol, glutathione, and N-acetylcysteine adducts of U-97924 supported the hypothesis of a reaction pathway involving reactive iminium species formed via dehydration of U-97924. The metabolism-dependent irreversible covalent binding of radioactive material to liver microsomal protein and DNA also is dramatically reduced in the presence of reduced glutathione (GSH). A trifluoromethyl analog of U-89843 was prepared in an effort to block the corresponding metabolic hydroxylation pathway. This new compound (U-107634) was found to be negative in the in vitro UDS assay, and its metabolic susceptibility toward hydroxylation at the C-6 methyl group was eliminated. These observations suggest that the positive in vitro UDS results of U-89843 are mediated by the bioactivation of U-89843, leading to reactive electrophilic intermediates derived from the (hydroxymethyl)pyrrole metabolite U-97924. |
| Databáze: | OpenAIRE |
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