Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man.

Bosma, Piter J.; Seppen, Jurgen; Goldhoorn, Bart; Bakker, C. M.; Elferink, Ronald P.J. Oude; Chowdhury, Jayanta Roy; Chowdhury, Namita Roy; Jansen, Petér L. M.

doi:10.1016/s0021-9258(17)32403-1

Cited by 389 publications

(45 citation statements)

References 31 publications

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“…3) suggested that bilirubin UGT may also be glucuronidating SN-38. The cDNAs of two forms of human liver bilirubin UGT have been cloned (41), with reports of one isoform (B-UGT 1 or UGT1A1) being physiologically relevant in bilirubin glucuronidation (46). To resolve this in reference to SN-38, HK293 cells expressing these specific isozymes were screened for SN-38 UGT activity.…”

Section: Discussionmentioning

confidence: 99%

Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes.

Iyer¹,

King²,

Whitington³

et al. 1998

J. Clin. Invest.

618

372

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Irinotecan (CPT-11) is a promising antitumor agent, recently approved for use in patients with metastatic colorectal cancer. Its active metabolite, SN-38, is glucuronidated by hepatic uridine diphosphate glucuronosyltransferases (UGTs). The major dose-limiting toxicity of irinotecan therapy is diarrhea, which is believed to be secondary to the biliary excretion of SN-38, the extent of which is determined by SN-38 glucuronidation. The purpose of this study was to identify the specific isoform of UGT involved in SN-38 glucuronidation. In vitro glucuronidation of SN-38 was screened in hepatic microsomes from normal rats (n = 4), normal humans (n = 25), Gunn rats (n = 3), and patients (n = 4) with Crigler-Najjar type I (CN-I) syndrome. A wide intersubject variability in in vitro SN-38 glucuronide formation rates was found in humans. Gunn rats and CN-I patients lacked SN-38 glucuronidating activity, indicating the role of UGT1 isoform in SN-38 glucuronidation. A significant correlation was observed between SN-38 and bilirubin glucuronidation (r = 0.89; P = 0.001), whereas there was a poor relationship between para-nitrophenol and SN-38 glucuronidation (r = 0.08; P = 0.703). Intact SN-38 glucuronidation was observed only in HK293 cells transfected with the UGT1A1 isozyme. These results demonstrate that UGT1A1 is the isoform responsible for SN-38 glucuronidation. These findings indicate a genetic predisposition to the metabolism of irinotecan, suggesting that patients with low UGT1A1 activity, such as those with Gilbert's syndrome, may be at an increased risk for irinotecan toxicity.

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Section: Discussionmentioning

confidence: 99%

Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes.

Iyer¹,

King²,

Whitington³

et al. 1998

J. Clin. Invest.

618

372

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“…The analysis of recombinant UGT cDNAs has shown that UGT1A proteins favour xenobiotic substrates, including a wide range of phenolic compounds, flavones and amines [12,13,18,20,21]. Some of these UGTs have unique catalytic activities catalysed by the bilirubin UGT1A1 [22], tertiary amine UGT1A4 [23] and oestrone UGT1A3 and UGT1A10 [13,18]. Conversely, recombinant UGT2B proteins exhibit a preference for endobiotic substrates, including hydroxylated steroids and bile acids [4,[6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Regulation and function of family 1 and family 2 UDP-glucuronosyltransferase genes (UGT1A, UGT2B) in human oesophagus

Strassburg¹,

STRASSBURG²,

Nguyen³

et al. 1999

Biochem. J.

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Human UDP-glucuronosyltransferases (UGTs) are expressed in a tissue-specific fashion in hepatic and extrahepatic tissues [Strassburg, Manns and Tukey (1998) J. Biol. Chem. 273, 8719-8726]. Previous work suggests that these enzymes play a protective role in chemical carcinogenesis [Strassburg, Manns and Tukey (1997) Cancer Res. 57, 2979-2985]. In this study, UGT1 and UGT2 gene expression was investigated in human oesophageal epithelium and squamous-cell carcinoma in addition to the characterization of individual UGT isoforms using recombinant protein. UGT mRNA expression was characterized by duplex reverse transcriptase-PCR analysis and revealed the expression of UGT1A7, UGT1A8, UGT1A9 and UGT1A10 mRNAs. UGT1A1, UGT1A3, UGT1A4, UGT1A5 and UGT1A6 transcripts were not detected. UGT2 expression included UGT2B7, UGT2B10 and UGT2B15, but UGT2B4 mRNA was absent. UGT2 mRNA was present at significantly lower levels than UGT1 transcripts. This observation was in agreement with the analysis of catalytic activities in oesophageal microsomal protein, which was characterized by high glucuronidation rates for phenolic xenobiotics, all of which are classical UGT1 substrates. Whereas UGT1A9 was not regulated, differential regulation of UGT1A7 and UGT1A10 mRNA was observed between normal oesophageal epithelium and squamous-cell carcinoma. Expression and analysis in vitro of recombinant UGT1A7, UGT1A9, UGT1A10, UGT2B7 and UGT2B15 demonstrated that UGT1A7, UGT1A9 and UGT1A10 catalysed the glucuronidation of 7-hydroxybenzo(alpha)pyrene, as well as other environmental carcinogens, such as 2-hydroxyamino-1-methyl-6-phenylimidazo-(4, 5-beta)-pyridine. Although UGT1A9 was not regulated in the carcinoma tissue, the five-fold reduction in 7-hydroxybenzo(alpha)pyrene glucuronidation could be attributed to regulation of UGT1A7 and UGT1A10. These data elucidate an individual regulation of human UGT1A and UGT2B genes in human oesophagus and provide evidence for specific catalytic activities of individual human UGT isoforms towards environmental carcinogens that have been implicated in cellular carcinogenesis.

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“…It was mainly built with the purpose to describe changes in the formation CL of acetaminophen metabolites throughout pregnancy. Changes in UGT1A1, SULT1A1 and CYP2E1 enzyme activity throughout pregnancy, built in this model, were obtained from the literature [ 15 , 28 , 40 , 41 , 42 , 43 ]. The implemented pregnancy-induced changes in UGT1A1 activity relied on reported in vivo serum trough concentrations of bilirubin, an exclusive substrate of UGT1A1 [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

“…Changes in UGT1A1, SULT1A1 and CYP2E1 enzyme activity throughout pregnancy, built in this model, were obtained from the literature [ 15 , 28 , 40 , 41 , 42 , 43 ]. The implemented pregnancy-induced changes in UGT1A1 activity relied on reported in vivo serum trough concentrations of bilirubin, an exclusive substrate of UGT1A1 [ 40 ]. The free-bilirubin trough concentration was, on average, 25%, 43%, and 48% lower in the first, second and third trimester, respectively, compared to that of non-pregnant women [ 41 ].…”

Section: Resultsmentioning

confidence: 99%

Modelling Tools to Characterize Acetaminophen Pharmacokinetics in the Pregnant Population

et al. 2021

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This review describes acetaminophen pharmacokinetics (PK) throughout pregnancy, as analyzed by three methods (non-compartmental analyses (NCA), population PK, and physiologically based PK (PBPK) modelling). Eighteen studies using NCA were reported in the scientific literature. These studies reported an increase in the volume of distribution (3.5–60.7%) and an increase in the clearance (36.8–84.4%) of acetaminophen in pregnant women compared to non-pregnant women. Only two studies using population PK modelling as a technique were available in the literature. The largest difference in acetaminophen clearance (203%) was observed in women at delivery compared to non-pregnant women. One study using the PBPK technique was found in the literature. This study focused on the formation of metabolites, and the toxic metabolite N-acetyl-p-benzoquinone imine was the highest in the first trimester, followed by the second and third trimester, compared with non-pregnant women. In conclusion, this review gave an overview on acetaminophen PK changes in pregnancy. Also, knowledge gaps, such as fetal and placenta PK parameters, have been identified, which should be explored further before dosing adjustments can be suggested on an evidence-based basis.

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Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man.

Cited by 389 publications

References 31 publications

Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes.

Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes.

Regulation and function of family 1 and family 2 UDP-glucuronosyltransferase genes (UGT1A, UGT2B) in human oesophagus

Modelling Tools to Characterize Acetaminophen Pharmacokinetics in the Pregnant Population

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