The stimulatory effect of morphine on reduction of naltrexone to 6 alpha-naltrexol in the guinea pig.
The enzymatic reduction of naltrexone proceeds more rapidly for formation of 6 alpha- than 6 beta-naltrexol in vitro in the guinea pig hepatic cytosol preparation. This paper describes the effect shown by addition of morphine to this formation; stimulation of the stereo-selective formation of 6 alpha-naltrexol. The enzyme activity for formation of 6 alpha-naltrexol was greatest in the 50--70% ammonium sulfate-precipitated fraction, whereas that for 6 beta-naltrexol formation peaked in the 40--60% fraction. When the 60--70% ammonium sulfate fraction was incubated with naltrexone, it was found that the Vmax was greatest for formation of 6 alpha-naltrexol when NADPH was added as the cofactor, less with the glucose-6-phosphate dehydrogenase NADPH-generating system, and least with NADH. When 10 mM morphine was added, the stimulation of 6 alpha-naltrexol formation occurred when either NADPH or NADH was added as cofactor. Inasmuch as enzyme activity with NADH in the absence of morphine was low, the relative stimulation by morphine was greater for the NADH than for the NADPH system. Also, when both NADPH and NADH were added in the same assay mixture, the predominant effect appeared to be manifested by the NADH system. Experiments in vivo indicated that coadministration of morphine intravenously with 3H-naltrexone did not produce stimulation of 6 alpha-naltrexol formation as measured in either bile or urine. On the other hand, the previous results on stimulation of 6 alpha-naloxol formation from naloxone were confirmed in vivo.
D000818:Animals; D006168:Guinea Pigs; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009243:NAD; D009249:NADP; D009270:Naloxone / Q000031:analogs & derivatives*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000378:metabolism*
D009243:NAD; D009270:Naloxone; C010410:6 beta-hydroxynaltrexone; D009249:NADP; D009271:Naltrexone; D009020:Morphine