Morphine metabolism revisited. III. Confirmation of a novel metabolic pathway.
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.
G
G
Krowech
P S
PS
Caldera-Munoz
K
K
Straub
N
N
Castagnoli
M A
MA
Correia
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000378:metabolism*; D009020:Morphine / Q000378:metabolism*; D051381:Rats; D013045:Species Specificity; D014316:Tritium
D014316:Tritium; D009020:Morphine