Morphine metabolism revisited: I. Metabolic activation of morphine to a reactive species in rats.
Treatment of fasted rats with relatively high doses of morphine rapidly results in depletion of hepatic glutathione (GSH) content and marked elevation of serum transaminase activity. Such morphine-induced response has been generally attributed to central nervous system mediated effects of the drug. We now report that this response might be due to a direct effect of the drug in the liver. That is, its metabolic activation to reactive electrophilic metabolite(s), by the hepatic cytochrome P-450-dependent mixed function oxidase system. Structure-activity relationships of morphine and its congeners indicate that the (-)-3-hydroxy-N- methylmorphinan moiety is linked with the potential of these opioids to deplete hepatic GSH and to raise serum transaminases in rats.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004090:Dihydromorphine / Q000378:metabolism; D004790:Enzyme Induction; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D009020:Morphine / Q000378:metabolism* / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism; D017450:Receptors, Opioid, mu
D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C028485:dihydromorphine receptor; D008748:Methylcholanthrene; D009020:Morphine; D003577:Cytochrome P-450 Enzyme System; D004090:Dihydromorphine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D010634:Phenobarbital