The enantioselective glucuronidation of morphine in rats and humans. Evidence for the involvement of more than one UDP-glucuronosyltransferase isoenzyme.
The formation of morphine glucuronides is enantio- and regioselective in rats and humans. In rat liver microsomes, natural (-)-morphine formed only the 3-O-glucuronide, whereas the unnatural (+)-morphine formed glucuronides at both the 3-OH and 6-OH positions, with the 6-O-glucuronide being the principal product. In human liver microsomes, both the 3-OH-and 6-OH positions were glucuronidated with each of the enantiomers, with the 3-O-glucuronide being the major product with (-)-morphine, and the 6-OH position preferred with the (+)-enantiomer. By using a series of biochemical and biological situations such as induction by xenobiotics, ontogeny, selective inhibition and genetic deficiencies, which are considered to be diagnostic of UDP-glucuronosyltransferase heterogeneity, we determined that two UDP-glucuronosyltransferase isoenzymes were responsible for the glucuronidation of morphine in rat liver. One isoenzyme (the so-called "morphine UDP-glucuronosyltransferase") was responsible for the glucoronidation at the (-)-3-OH and (+)-6-OH positions of morphine, whereas the other formed only the (+)-morphine-3-glucuronide. Evidence from enzyme induction and the genetically deficient deficient Gunn rat suggested that bilirubin UDPGT may be responsible for the (+)-morphine-3-UDP-glucuronosyltransferase activity. In human kidney, glucuronidation of both (-)- and (+)-enantiomers at the 6-OH position was deficient, whereas the activity at the 3-OH positions was still present, which indicated the involvement of two UDP-glucuronosyltransferases in the glucuronidation of morphine in man, as well as rats.
Coughtrie
M W
MW
Department of Biochemistry, The University, Dundee, U.K.
Ask
B
B
Rane
A
A
Burchell
B
B
Hume
R
R
D000367:Age Factors; D000818:Animals; D002994:Clofibrate / Q000494:pharmacology; D004790:Enzyme Induction; D014453:Glucuronosyltransferase / Q000032:analysis*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000032:analysis*; D008099:Liver / Q000201:enzymology; D008297:Male; D009020:Morphine / Q000378:metabolism*; D009022:Morphine Derivatives / Q000378:metabolism*; D009280:Naphthaleneacetic Acids / Q000494:pharmacology; D051381:Rats; D011911:Rats, Gunn; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D007527:Isoenzymes; D009022:Morphine Derivatives; D009280:Naphthaleneacetic Acids; C034182:1-naphthaleneacetic acid; C035349:morphine-6-glucuronide; D009020:Morphine; D014453:Glucuronosyltransferase; D002994:Clofibrate; C018108:morphine-3-glucuronide