Morphine metabolism revisited. II. Isolation and chemical characterization of a glutathionylmorphine adduct from rat liver microsomal preparations.
Incubation of tritium-labeled morphine and cold glutathione (GSH) or cold morphine and tritiated GSH with liver microsomal preparations obtained from phenobarbital-treated rats led to the identification by high performance liquid chromatography (HPLC) of a glutathionylmorphine adduct. Liquid secondary ion mass spectral analysis established the molecular weight of the metabolite to be 590 which corresponds to the mass of a mono-GSH-morphine adduct. High resolution (360 and 500 MHz) 1H-NMR experiments have led to the tentative assignment of the structure of this metabolite as 10-alpha-S-glutathionylmorphine. Based on both in vivo and in vitro data, the formation of this product appears to be mediated by cytochrome P-450 and to involve a reactive intermediate that may be responsible for the observed covalent binding of radiolabeled morphine to proteins and, at least in part, for the morphine-induced depletion of GSH in the rat.
D000818:Animals; D005978:Glutathione / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009020:Morphine / Q000378:metabolism*; D009022:Morphine Derivatives / Q000302:isolation & purification*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D014316:Tritium
D009022:Morphine Derivatives; D014316:Tritium; D009020:Morphine; C042444:10-alpha-S-glutathionylmorphine; D005978:Glutathione; D010634:Phenobarbital