| Abstract: | Previous studies have led to the partial structural characterization of a glutathionylmorphine adduct which was isolated from rat liver microsomal incubations. The formation of this adduct was shown to be catalyzed by cytochrome P-450. As an extension of this work, we have carried out similar studies with N-acetylcysteine in an attempt to obtain a product amenable to complete NMR analysis and unambiguous structure assignment. Incubation of [3H]morphine and N-acetylcysteine with microsomal preparations isolated from human and from phenobarbital-treated rats led to the isolation by HPLC of a labeled species displaying a fast atom bombardment mass spectrum consistent with the expected N-acetylcysteinyl adduct of morphine. Data obtained from the high resolution 1H-NMR spectrum of the adduct and that of synthetic 10 alpha-hydroxycodeine established the structure of the metabolite as 10 alpha-S-(N-acetylcysteinyl)morphine. The results are consistent with the biotransformation of morphine involving oxidation at the benzylic C-10 position to form an electrophilic species capable of reacting with nucleophilic thiols such as N-acetylcysteine and glutathione. |
