The Biotransformation of Nitrogen Containing Xenobiotics to Lactams

摘要: The metabolism of nitrogen heterocyclics may lead to lactam formation. In early studies on xenobiotic lactams were identified as metabolites nicotine, cyproheptadine, tremorine and prolintane. Now, because the increasing availability powerful analytical techniques, there are many instances being metabolites. Lactam formed from either iminium ions or carbinolamines. These two intermediates have distinct mechanisms formation but they can interconvert. There is evidence that oxidized by aldehyde oxidases (cytosolic molybdenum hydroxylases). tissue distribution enzyme activities oxidase been studied in several animal species. However, it also known undergo spontaneous hydrolysis corresponding carbinolamine. If latter stable oxidation cytochrome P-450 form lactam. Thus, species differences might be caused concentrations P450 isozymes oxidases. It appears an end stage N-heterocycles unlikely will amino acid. Such acids probably arise aldehydes produced ring opening unstable carbinolamine intermediates. When microsomal preparations incubated with appropriate substrate presence sodium cyanide ion trapped produce a cyano compound. reactions led proposal react nucleophilic sites cellular macromolecules so contribute both pharmacology toxicology N-heterocyclic compounds. Other pathways for involve internal cyclization precursor metabolites, e.g. self-condensation group (formed during metabolism) neighboring amide group. closures seem since would anticipated acid residue exist zwitterion under physiological conditions. futile via hydrolytic followed closure. Under extreme conditions such unanticipated occur metabolite isolation occurrence artifacts.