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

doi:10.1016/0006-2952(89)90625-4

Biochemical Pharmacology

Volume 38, Issue 19, 1 October 1989, Pages 3273-3280

https://doi.org/10.1016/0006-2952(89)90625-4 Get rights and content

Abstract

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 glucuronidation 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 (+) morphine3-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.

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Major enzyme systems involved in the biotransformation of xenobiotics via hepatic oxidative (phase I) and conjugative (phase II) pathways are reviewed in the context of physiological and anatomical features that influence these pathways in the intact liver in vivo. Enzyme systems belonging to the phase I category discussed in this chapter include members of the cytochrome P450 (CYP) gene superfamily, flavin monooxygenases (FMOs), aldo–keto reductases (AKRs), short-chain dehydrogenases (SDRs), NAD(P) quinone oxidoreductases (NQO1 and NQO2), and epoxide hydrolase. Enzyme systems catalyzing phase II reactions discussed include uridine diphosphate-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), glutathione-S-transferases (GSTs), N-acetyltransferases (NATs), and N- and O-methyltransferases. Catalysis of amino acid conjugation via acyl-CoA thioethers or aminoacyl-tRNA synthetase is also reviewed. Enzymes implicated in phase II deconjugating reactions including β-glucuronidase, arylsulfatase-c, and carboxylesterases/amidases are also discussed. A final section considers the potential function of cofactor supply in limiting phase I and phase II biotransformation reactions in intact hepatocytes focusing on reactions regulating the formation of NADPH required for phase I monooxygenation and the generation of activated cofactors such as uridine-diphosphoglucuronic acid (UDPGA) and 3′-phosphoadenosine-5′-phosphosulfate (PAPS) required for phase II conjugation reactions.

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^∗: Present address:Department of Biochemical Medicine,Ninewells Hospital and Medical School,The University,Dundee DD1 9sy, U.K.

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

Abstract

J Chromatogr

J Biol Chem

Biochem Pharmacol

Biochem Pharmacol

FEBS Lett

Natural (-)- and unnatural (+)-enantiomers of morphine: comparative metabolism and effect of morphine and phenobarbital treatment

J Pharmacol Exp Ther

Morphine UDP-glucuronosyltransferase in rat and human liver

Acta Pharm Toxicol

Differential hepatic glucuronidation of (−) and (+)-morphine in the rat and the human fetus

Purification of rat liver microsomal UDP-glucuronosyltransferase. Separation of two enzyme forms inducible by 3-methylcholanthrene and phenobarbital

Eur J Biochem

Defective induction of phenol glucuronidation by 3-methylcholanthrene in Gunn rats is due to the absence of a specific UDP-glucuronosyltransferase isoenzyme

Mol Pharmacol