Production of morphinone as a metabolite of morphine and its physiological role

Morphine is a potent analgesic and is widely used in the clinical management of severe acute and chronic pain; however, its clinical usefulness is limited due to the development of both tolerance and dependence after repeated morphine administration. The morphine metabolism has been studied in order to elucidate its pharmacological actions as well as its adverse effects. Thus far several metabolites have been identified and their analgesic potency and toxicity have been also investigated. In the toxicological viewpoint, the production of reactive metabolites that can bind cellular glutathione and protein has been postulated. We found morphine 6-dehydrogenase, which catalyzes the dehydrogenation of 6-hydroxy group of morphine to produce morphinone, in the guinea pig liver. It was also found that morphinone antagonizes the morphine analgesia and binds with glutathione and protein. We here demonstrate the presence of a metabolic pathway of morphine to morphinone and subsequently to morphinone-glutathione adduct, and compare the property including primary structure among the guinea pig, rabbit, mouse and hamster liver morphine 6-dehydrogenases. We also describe the toxicological significance of morphinone.