The enantioselective glucuronidation of morphine in rats and humans. Evidence for the involvement of more than one UDP-glucuronosyltransferase isoenzyme

Biochem Pharmacol. 1989 Oct 1;38(19):3273-80. doi: 10.1016/0006-2952(89)90625-4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Clofibrate / pharmacology
  • Enzyme Induction
  • Glucuronosyltransferase / analysis*
  • Humans
  • In Vitro Techniques
  • Isoenzymes / analysis*
  • Liver / enzymology
  • Male
  • Morphine / metabolism*
  • Morphine Derivatives / metabolism*
  • Naphthaleneacetic Acids / pharmacology
  • Rats
  • Rats, Gunn
  • Rats, Inbred Strains
  • Stereoisomerism


  • Isoenzymes
  • Morphine Derivatives
  • Naphthaleneacetic Acids
  • 1-naphthaleneacetic acid
  • morphine-6-glucuronide
  • Morphine
  • Glucuronosyltransferase
  • Clofibrate
  • morphine-3-glucuronide