Common Human <i>UGT1A</i> Polymorphisms and the Altered Metabolism of Irinotecan Active Metabolite 7-Ethyl-10-hydroxycamptothecin (SN-38)

Gagné, Jean-François; Montminy, Valérie; Bélanger, Patrick; Journault, Kim; Gaucher, Geneviève; Guillemette, Chantal

doi:10.1124/mol.62.3.608

Cited by 324 publications

(256 citation statements)

References 33 publications

(47 reference statements)

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“…Physiological function of UGT1A_i2 spliced forms J Bellemare et al described 6,7,11,12 and was reported as glucuronidation rates (area or pmol min -1 mg -1 protein).…”

Section: Glucuronide Formation Was Measured By Hplc-ms/ms Asmentioning

confidence: 99%

Alternative-splicing forms of the major phase II conjugating UGT1A gene negatively regulate glucuronidation in human carcinoma cell lines

et al. 2009

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The UDP-glucuronosyltransferase UGT1A gene is a major biotransformation gene involved in the metabolism of a vast array of molecules. Recently, we uncovered a new series of alternative spliced isoforms referred to as isoforms 2 or UGT1As_i2 that use an alternative exon 5 (5b). The function of such mRNAs and the corresponding 45 kDa proteins still remains unclear. Although devoid of glucuronosyltransferase activity, UGT1As_i2 are widely co-expressed with the enzymatically active and classical UGT1A isoforms (UGT1As_i1). In this study, we observed abundant signal in human colon tissue samples, predominantly along intestinal crypts. In human cells, UGT1A_i2 proteins are expressed in similar subcellular compartments as UGT1As_i1. Cellular properties of i2-spliced forms were then studied using synthetic small-interfering RNA (siRNA) in two human colon cancer cell lines that show a significant amount of exon 5a-and exon 5b-containing mRNAs and that display enzymatic activities for UGT1As substrates. We observed that siRNA-mediated knockdown of endogenous i2 upregulates cellular glucuronidation activities by 120-170% (Po0.01) for all substrates tested. Functional data support a dominant-negative function for endogenous exon 5b-spliced forms of UGT1A, hence potentially affecting in vivo glucuronidation capacity. This new regulatory strategy may ensure an additional mean to modulate cellular response to endo/xeno stimulus.

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“…Physiological function of UGT1A_i2 spliced forms J Bellemare et al described 6,7,11,12 and was reported as glucuronidation rates (area or pmol min -1 mg -1 protein).…”

Section: Glucuronide Formation Was Measured By Hplc-ms/ms Asmentioning

confidence: 99%

Alternative-splicing forms of the major phase II conjugating UGT1A gene negatively regulate glucuronidation in human carcinoma cell lines

et al. 2009

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“…64 This is consistent with the recent observation showing that the impact of the UGT1A1*6 allele on in vitro rates of SN-38 glucuronidation is modest compared to that observed for UGT1A1*27. 62 The hepatic UGT1A9 and the extrahepatic UGT1A7 enzymes were recently shown to be involved in the in vitro metabolism of SN-38. 62 Thus, polymorphisms in UGT1A7 and UGT1A9 along with the promoter polymorphism of UGT1A1 and functional SNPs present in its coding region, potentially represent significant risk factors for severe toxicity and could serve to predict the incidence of adverse events in patients undergoing irinotecan-based chemotherapy.…”

Section: Ugt1a1mentioning

confidence: 99%

“…Recent work has demonstrated that genetic variations affect glucuronidation rates and influence the risk of an individual to develop drug-induced toxicity. 35,37,[61][62][63][64] The role of genetic factors in determining variable rates of glucuronidation of hormones, tobacco smoke carcinogens, environmental pollutants and dietary components is poorly understood. Recent findings suggest that metabolic alterations may actually determine the degree of exposure of an individual to toxic or carcinogenic substances over a long time period and may contribute to modify one's susceptibility to diseases such as cancer.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

2003

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UDP-glucuronosyltransferase (UGT) enzymes comprise a superfamily of key proteins that catalyze the glucuronidation reaction on a wide range of structurally diverse endogenous and exogenous chemicals. Glucuronidation is one of the major phase II drug-metabolizing reactions that contributes to drug biotransformation. This biochemical process is also involved in the protection against environmental toxicants, carcinogens, dietary toxins and participates in the homeostasis of numerous endogenous molecules, including bilirubin, steroid hormones and biliary acids. Over the years, significant progress was made in the field of glucuronidation, especially with regard to the identification of human UGTs, study of their tissue distribution and substrate specificities. More recently, the degree of allelic diversity has also been revealed for several human UGT genes. Some polymorphic UGTs have demonstrated a significant pharmacological impact in addition to being relevant to drug-induced adverse reactions and cancer susceptibility. This review focuses on human UGTs, the description of the nature of polymorphic variations and their functional impact. The pharmacogenomic implication of polymorphic UGTs is presented, more specifically the role of UGT polymorphisms in modifying cancer risk and their impact on individual risk to drug-induced toxicities.

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“…(8) In addition to UGT1A1, other human UGT isoforms (e.g., UGT1A7 and UGT1A9) appear to catalyze SN-38G formation. (9,10) In addition to metabolism, another important route of irinotecan elimination is through biliary excretion. Among the several ABC transporters, ABCB1 and ABCC2 are the two main transporters involved in the biliary elimination of irinotecan and SN-38 species.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic Pathway Analysis of Irinotecan

Rosner

Panetta

Innocenti

et al. 2008

Clin Pharmacol Ther

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Irinotecan, a chemotherapeutic agent for various solid tumors, is a prodrug requiring activation to SN-38. Irinotecan's complex pharmacokinetics allows for potentially many genetic sources of variability. We explored relationships between pharmacokinetic pathways and polymorphisms in genes associated with irinotecan's metabolism and transport. We fit a seven-compartment pharmacokinetic model with enterohepatic recirculation to concentrations of irinotecan and metabolites SN-38, SN-38G (glucuronide), and APC. Principal component analysis (PCA) of patientspecific parameter estimates produced measures interpretable along pathways. Nine principal components characterized overall variation well. Polymorphisms in genes UGT1A1, UGT1A7, and UGT1A9 had strong associations with a component corresponding to the irinotecan-to-SN-38 pathway and SN-38 recirculation and to a component relating to SN-38-to-SN-38G conversion and SN-38G's elimination. The component characterizing irinotecan's compartments was associated with HNF1α and ABCC2 polymorphisms. The exploratory analysis with PCA in this pharmacogenetic analysis identified known associations and may have allowed identification of previously uncharacterized functional polymorphisms.

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Common Human UGT1A Polymorphisms and the Altered Metabolism of Irinotecan Active Metabolite 7-Ethyl-10-hydroxycamptothecin (SN-38)

Cited by 324 publications

References 33 publications

Alternative-splicing forms of the major phase II conjugating UGT1A gene negatively regulate glucuronidation in human carcinoma cell lines

Alternative-splicing forms of the major phase II conjugating UGT1A gene negatively regulate glucuronidation in human carcinoma cell lines

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

Pharmacogenetic Pathway Analysis of Irinotecan

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