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PubMed · 11868392

[UDP-glucuronosyltransferase].

Yoshihiro Maruo·Hiroshi Sato
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Abstract

UDP-glucuronosyltransferases (UGTs) represent a family of enzymes that glucuronidate many internal substances and drugs. This family acts as a drug metabolism phase II reactor in the liver and comprises one of the major protective mechanisms from toxic chemical substances. UGTs have two subfamilies; UGT1 and UGT2. UGT1 gene expresses 12 isoforms which are produced from a single gene by alternative splicing of a primary transcript. Each isoform has specific substrates. UGT1A1 conjugates bilirubin, and mutations of the gene cause hereditary unconjugated hyperbilirubinemias (Crigler-Najjar syndrome and Gilbert's syndrome). Recently, polymorphisms of UGT1A1 were revealed. In the Japanese population, there is a polymorphism of G71R and this mutation is a risk factor of neonatal hyperbiliruibnemia and a genetic cause of breast milk jaundice. These polymorphisms of UGTs might contribute to individual variations of drug metabolism and toxicity as well as inherited diseases.

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GlucuronosyltransferaseHumansHyperbilirubinemiaUGT1A1 EnzymeEnglish AbstractJournal ArticleReview

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Yoshihiro Maruo, Hiroshi Sato. 2002. [UDP-glucuronosyltransferase].. https://pubmed.ncbi.nlm.nih.gov/11868392/

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Glucuronosyltransferase↗
PubMed2005

S-Naproxen and desmethylnaproxen glucuronidation by human liver microsomes and recombinant human UDP-glucuronosyltransferases (UGT): role of UGT2B7 in the elimination of naproxen.

AIMS: To characterize the kinetics of S-naproxen ('naproxen') acyl glucuronidation and desmethylnaproxen acyl and phenolic glucuronidation by human liver microsomes and identify the human UGT isoform(s) catalysing these reactions. METHODS: Naproxen and desmethylnaproxen glucuronidation were investigated using microsomes from six and five livers, respectively. Human recombinant UGTs were screened for activity towards naproxen and desmethylnaproxen. Where significant activity was observed, kinetic parameters were determined. Naproxen and desmethylnaproxen glucuronides were measured by separate high-performance liquid chromatography methods. RESULTS: Naproxen acyl glucuronidation by human liver microsomes followed biphasic kinetics. Mean apparent K(m) values (+/-SD, with 95% confidence interval in parentheses) for the high- and low-affinity components were 29 +/- 13 microm (16, 43) and 473 +/- 108 microm (359, 587), respectively. UGT 1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10 and 2B7 glucuronidated naproxen. UGT2B7 exhibited an apparent K(m) (72 microm) of the same order as the high-affinity human liver microsomal activity, which was inhibited by the UGT2B7 selective 'probe' fluconazole. Although data for desmethylnaproxen phenolic glucuronidation by human liver microsomes were generally adequately fitted to either the single- or two-enzyme Michaelis-Menten equation, model fitting was inconclusive for desmethylnaproxen acyl glucuronidation. UGT 1A1, 1A7, 1A9 and 1A10 catalysed both the phenolic and acyl glucuronidation of desmethylnaproxen, while UGT 1A3, 1A6 and 2B7 formed only the acyl glucuronide. Atypical glucuronidation kinetics were variably observed for naproxen and desmethylnaproxen glucuronidation by the recombinant UGTs. CONCLUSION: UGT2B7 is responsible for human hepatic naproxen acyl glucuronidation, which is the primary elimination pathway for this drug.

Glucuronosyltransferase↗