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 Genotoxicity1

Autor:	Schwartz Tm, G L Bundy, K A Koeplinger, J. K. Mayo, G. E. Padbury, Zhiyang Zhao, Harbach Pr, Zimmermann Dc, C.S. Aaron, M J Hauer, L S Banitt
Rok vydání:	1996
Předmět:	Antioxidant Pyrimidine Chemistry DNA damage Stereochemistry DNA repair medicine.medical_treatment Reactive intermediate General Medicine Glutathione Toxicology chemistry.chemical_compound Biochemistry In vivo medicine Macromolecule
Zdroj:	Chemical Research in Toxicology. 9:1230-1239
ISSN:	1520-5010 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-...
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::ac451d727323d1cb8f441d48692d44a6 https://doi.org/10.1021/tx960092z Zobrazit plný text záznamu