Drug-mediated toxicity caused by genetic deficiency of UDP-glucuronosyltransferases

Burchell, Brian; Soars, Matt; Monaghan, Gemma; Cassidy, Andrew J.; Smith, D. J.; Ethell, Brian T.

doi:10.1016/s0378-4274(99)00209-x

Cited by 88 publications

(45 citation statements)

References 42 publications

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“…Glucuronidation renders the aglycone more water-soluble and facilitates its excretion from the body. Mutations that lead to low expression level or weak activity of UGT1A1 result in poor bilirubin glucuronidation and subsequent development of Crigler-Najjar or Gilbert's Syndromes (6,7). Mutations in UGT1A7 were suggested to increase the risk of colorectal cancer development (8), whereas UGT1A9 was shown to play an important role in the metabolism of certain carcinogenic amines (9).…”

Section: Udp-glucuronosyltransferases (Ugts)mentioning

confidence: 99%

Expression and Characterization of Recombinant Human UDP-glucuronosyltransferases (UGTs)

Kurkela¹,

Garcı́a-Horsman²,

Luukkanen³

et al. 2003

Journal of Biological Chemistry

139

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Eight human liver UDP-glucuronosyltransferases (UGTs) were expressed in baculovirus-infected insect cells as fusion proteins carrying a short C-terminal extension that ends with 6 histidine residues (His tag). The activity of recombinant UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT2B4, UGT2B7, and UGT2B15 was almost fully inhibited by 0.2% Triton X-100. In the case of UGT1A9, however, glucuronidation of ␣-naphthol and scopoletin was resistant to such inhibition, whereas glucuronidation of entacapone and several other aglycones was sensitive. His-tagged UGT1A9 was purified by immobilized metal-chelating chromatography (IMAC). Purified UGT1A9 glucuronidated scopoletin at a high rate, whereas its glucuronidation activity toward entacapone was low and largely dependent on phospholipid addition. Recombinant UGT1A9 in which the His tag was replaced by hemagglutinin antigenic peptide (HA tag) was also prepared. Insect cells were co-infected with baculoviruses encoding both HA-tagged and His-tagged UGT1A9. Membranes from the co-infected cells, or a mixture of membranes from separately infected cells, were subjected to detergent extraction and IMAC, and the resulting fractions were analyzed for the presence of each type of UGT1A9 using tag-specific antibodies. In the case of separate infection, the HA-tagged UGT1A9 did not bind to the column. When co-infected with Histagged UGT1A9, however, part of the HA-tagged enzyme was bound to the column and was eluted by imidazole concentration gradient together with the His-tagged UGT1A9, suggesting the formation of stable dimers that contain one His-tagged and one HA-tagged UGT1A9 monomers.

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Section: Udp-glucuronosyltransferases (Ugts)mentioning

confidence: 99%

Expression and Characterization of Recombinant Human UDP-glucuronosyltransferases (UGTs)

Kurkela¹,

Garcı́a-Horsman²,

Luukkanen³

et al. 2003

Journal of Biological Chemistry

139

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“…Also is very important to inform the patient on side effects or unexpected toxicity due to some drugs which metabolism is due to hepatic glucoronidation (18) (Table II).…”

Section: Discussionmentioning

confidence: 99%

Unusual presentation of Gilbert disease with high levels of unconjugated bilirubin. Report of two cases

et al. 2015

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Gilbert's syndrome is a benign condition characterized by asymptomatic sporadic episodes of jaundice, due to a mild unconjugated hyperbilirubinemia caused by a deficiency in bilirubin glucoronidation. Under certain physiologic or pathologic events, bilirubin level rises but according to literature it does not reach out more than 3 mg/dl. We report 2 cases of Gilbert's syndrome, genetically tested, which presented with bilirubin levels above 6 mg/dl without any trigger or coexisting condition. In conclusion, bilirubin levels higher than 6 mg/dl in Gilbert syndrome are rare, hemolytic and other metabolism diseases must be ruled out, and genetic testing may be necessary in some cases.

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“…The UGT1A1 gene has an important role in hepatic glucuronidation of several drugs prior to excretion. Diminished excretion of these non-metabolized drugs could potentially cause their accumulation and increase their toxicity (6), as has been previously described (18). It is possible that diminished hepatic glucuronidation of PEGv in individuals with Gilbert's syndrome could increase the risk of liver damage.…”

Section: Normal Rangementioning

confidence: 95%

Pegvisomant-induced cholestatic hepatitis with jaundice in a patient with Gilbert's syndrome

Bernabéu

Cameselle-Teijeiro

Casanueva

et al. 2009

European Journal of Endocrinology

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We report on a patient with active acromegaly and Gilbert's syndrome who developed severe hepatic dysfunction during pegvisomant (PEGv) monotherapy. She was partially resistant to all previous therapies, including long-acting somatostatin analogs and cabergoline. Five months after starting PEGv therapy, with an already normalized IGF1, she developed cholestatic liver dysfunction with jaundice. Liver or biliary diseases including biliary sludge, cholelithiasis or liver steatosis were excluded. A liver biopsy was in keeping with drug-induced liver injury. The discontinuation of PEGv was followed by full clinical and biochemical recovery in 6 weeks. PEGv therapy was not resumed. Apart from a minimal increase of bilirubin levels, no liver function test abnormalities were found during the 4-year follow-up period after the PEGv was discontinued. Drug-induced liver injury is the most serious systemic adverse event resulting from PEGv therapy. Since patients with mild and asymptomatic liver disease could be at a higher risk of PEGv-induced hepatotoxicity, frequent monitoring of hepatic enzymes should be required in these cases.

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Drug-mediated toxicity caused by genetic deficiency of UDP-glucuronosyltransferases

Cited by 88 publications

References 42 publications

Expression and Characterization of Recombinant Human UDP-glucuronosyltransferases (UGTs)

Expression and Characterization of Recombinant Human UDP-glucuronosyltransferases (UGTs)

Unusual presentation of Gilbert disease with high levels of unconjugated bilirubin. Report of two cases

Pegvisomant-induced cholestatic hepatitis with jaundice in a patient with Gilbert's syndrome

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