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Chantal Guillemette - One of the best experts on this subject based on the ideXlab platform.
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Microsoft Word - 6292384-file00.docx
2020Co-Authors: Michael H Court, Chantal Guillemette, Marina Freytsis, Xueding Wang, Inga Peter, Suwagmani Hazarika, Su X Duan, David J Greenblatt, William M Lee, Bvsc Michael H CourtAbstract:The UDP-Glucuronosyltransferase (UGT) 1A polymorphism c.2042C>G (rs8330) is associated with increased human liver acetaminophen glucuronidation, increased UGT1A exon 5a/5b splice variant mRNA ratio, and decreased risk of unintentional acetaminopheninduced acute liver failure
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clinical pharmacogenetics implementation consortium cpic guideline for ugt1a1 and atazanavir prescribing
Clinical Pharmacology & Therapeutics, 2016Co-Authors: Roseann S Gammal, Chantal Guillemette, Jeffrey L. Lennox, Michael H Court, Cyrine E Haidar, Otito F Iwuchukwu, Aditya H Gaur, Maria L Alvarellos, Michelle Whirlcarrillo, Sean BrummelAbstract:The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate Glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin-related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org).
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steroidogenesis and modifies the risk of prostate cancer progression
2016Co-Authors: Luciana Garcia, Chantal Guillemette, Lyne Villeneuve, Yves Frade, Louis Lacombe, David Simonya, Patrick Caro, Eric LevesqueAbstract:Background: Androgen inactivation occurs mainly through the glucuronidation conjugative reaction mediated by UDP-Glucuronosyltransferases (UGTs). This metabolic process is involved in the control of systemic and local androgen bioavailability. Objective: To examine the relationship among expression of the androgen-inactivating UGT2B28 enzyme, circulating steroid hormone levels, and clinical phenotype in prostate cancer (PCa). Design, setting, and participants: We conducted an analysis of a high-density prostate tumor tissue microarray consisting of 239 localized PCa cases. The study of 51 additional PCa patients with no copies of UDP Glucuronosyltransferase 2B subfamily, polypeptide B28 (UGT2B28) in their genomes was performed to confirm the importance of the enzyme on circulating hormone levels. Outcome measurements and statistical analysis: Steroid hormones were measured by mass spectrometry. Multivariate Cox proportional hazard models assessed the influence of UGT2B28 on progression, and general linear model regression evaluated variations in hormone levels. Results and limitations: Tumor overexpression of UGT2B28 was associated with lower prostate-specific antigen levels at diagnosis, higher Gleason scores, margin and nodal invasion status, and it was shown to be an independent prognostic factor associated with progression. Enzyme overexpression correlated with 30% higher circulating levels of testosterone (T) and dihydrotestosterone (DHT). Patients with no copies of UGT2B28 in their genomes have lower levels of T (19%), DHT (17%), its glucuronide metabolites (18–38%), and enhanced levels of the
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pharmacogenomics of human uridine diphospho Glucuronosyltransferases and clinical implications
Clinical Pharmacology & Therapeutics, 2014Co-Authors: Chantal Guillemette, Eric Levesque, Michele RouleauAbstract:Glucuronidation by uridine diphospho-Glucuronosyltransferase enzymes (UGTs) is a major phase II biotransformation pathway and, complementary to phase I metabolism and membrane transport, one of the most important cellular defense mechanisms responsible for the inactivation of therapeutic drugs, other xenobiotics, and endogenous molecules. Interindividual variability in UGT pathways is significant and may have profound pharmacological and toxicological implications. Several genetic and genomic processes underlie this variability and are discussed in relation to drug metabolism and diseases such as cancer.
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a pharmacogenetics study of the human Glucuronosyltransferase ugt1a4
Pharmacogenetics and Genomics, 2009Co-Authors: Marieodile Enoitbiancamano, Michael H Cou, Jeanphilippe Adam, Olivie Ernard, Mariehelene Leblanc, Patrick Caro, Chantal GuillemetteAbstract:Background UGT1A4 is primarily expressed in the liver and exhibits catalytic activities for various drugs. Amongst the few UGT1A4 polymorphisms evaluated, studies support the alteration of UGT1A4-mediated glucuronidation by a few variations including the Pro 24 Thr and Leu 48 Val variants (referred to as UGT1A4*2 and *3). Methods We therefore investigated genetic mechanisms that might contribute to interindividual variation in UGT1A4 expression and activity. The UGT1A4 gene was sequenced from -4963 bp relative to the ATG to 2000 bp after the first exon in 184 unrelated Caucasians and African-Americans. Results We identified a large number of genetic variations, including 13 intronic, 39 promoter, as well as 14 exonic polymorphisms, with 10 that lead to amino-acid changes. Of the nucleotide variations found in the -5 kb promoter region, five are located in the proximal region (first 500 bp), and positioned in putative HNF-1 and OCT-1 binding sites. Four of these variants, placed at -163, -219, -419 and -463, are in complete linkage disequilibrium with the Leu 48 Val coding region variant and with several variants in the upstream region of the promoter. Transient transfections of reference and variant promoter constructs (from position -500 to +1) in different cell lines with or without co-expression of HNF-1 and/or OCT-1 showed limited effect of these variations. Conclusion Additional functional studies on promoter variants are still required to predict their potential influence on UGT1A4 expression in vivo. Besides, several coding variants significantly modified the enzyme kinetics for tamoxifen and Z-4-hydroxytamoxifen (Val 48 , Asp 50 , Gln 56 , Phe 176 , Asn 250 , Leu 276 ) and are expected to have a potential in vivo effect.
Ida S Owens - One of the best experts on this subject based on the ideXlab platform.
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thirteen udpGlucuronosyltransferase genes are encoded at the human ugt1 gene complex locus
Pharmacogenetics, 2001Co-Authors: Qihui Gong, Jeong W Cho, Theresa Huang, Christine Potter, Nahid Gholami, Nikhil K Basu, Shigeki Kubota, Sheryl Carvalho, Matthew W Pennington, Ida S OwensAbstract:The original novel UGT1 complex locus previously shown to encode six different UDP-Glucuronosyltransferase (transferase) genes has been extended and demonstrated to specify a total of 13 isoforms. The genes are designated UGT1A1 through UGT1A13p with four pseudo ones. UGT1A2p and UGT1A11p through UG
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genetic polymorphism in the human ugt1a6 planar phenol udp Glucuronosyltransferase pharmacological implications
Pharmacogenetics, 1997Co-Authors: Marco Ciotti, Christine Potter, Aldo Marrone, Ida S OwensAbstract:Two missense mutations were uncovered in the IIGT1A6 (HLUG PI) cDNA which codes for a human phenol-metabolizing UDP-Glucuronosyltransferase. The mutant and a wild- type IJGT1A6 cDNAs were isolated from a custom synthesized human liver λ Zap cDNA library. Both an A to G transition at nucleotide 541 (
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altered coding for a strictly conserved di glycine in the major bilirubin udp Glucuronosyltransferase of a crigler najjar type i patient
Journal of Biological Chemistry, 1995Co-Authors: Marco Ciotti, Matthew T Yeatman, Ronald J Sokol, Ida S OwensAbstract:The characterization (Ritter, J. K., Chen, F., Sheen, Y. Y., Tran, H. M., Kimura, S., Yeatman, M. T., and Owens, I. S. (1992) J. Biol. Chem. 267, 3257-3261) of the single-copy UGT1 gene complex locus encoding both bilirubin and phenol UDP-Glucuronosyltransferases (transferase) has been critical to the determination of genetic defects in Crigler-Najjar patients. The complex (UGT1A-UGT1M) codes for at least two bilirubin, three bilirubin-like, and eight phenol transferase isozymes. In the 5′ region, a minimum of 13 different exons 1, each with an upstream promoter, are arrayed in series with 4 common exons in the 3′ region of the locus. Each exon 1 encodes the amino terminus of a transferase, and the common exons encode the common carboxyl terminus of each isoform. Although a deleterious mutation in a common exon inactivates the entire locus, a deleterious mutation in an exon 1, as we report here for the UGT1A gene in a Crigler-Najjar Type I patient, affects the amino terminus of that single isoform. Recessively inherited mutant alleles for the predominant bilirubin isozyme, the HUG-Br1 protein, substituted Arg for Gly at codon 276 (G276R) in exon 1 of UGT1A abolishing a conserved di-glycine. The mutant HUG-Br1-G276R protein expressed in COS-1 cells had no detectable bilirubin glucuronidating activity at either pH 7.6 or 6.4. Although each of the bilirubin-type isozymes contains a conserved peptide between residues 270 and 288, all UDP-Glucuronosyltransferases contain a di-glycine at approximately position 276-277, making it strictly conserved. Structure-function relationship was studied by site-directed mutations of the HUG-Br1 cDNA; G276A, G276Q, G276E, G276I, and P270G mutants were inactive, and V275I- and P285G-altered transferases expressed normal activity. Conservation of residues between the related baculoviral ecdysone UDP-glucosyltransferase and the UDP-Glucuronosyltransferases confirms the critical role of the Gly-276 as well as other residues.
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cloning of two human liver bilirubin udp Glucuronosyltransferase cdnas with expression in cos 1 cells
Journal of Biological Chemistry, 1991Co-Authors: Joseph K Ritter, J M Crawford, Ida S OwensAbstract:We report the isolation and characterization of two human liver cDNA clones, HUG-Br1 and HUG-Br2; each encodes a UDP-Glucuronosyltransferase enzyme which glucuronidates bilirubin IX alpha to form both the IX alpha C8 and IX alpha C12 monoconjugates and a diconjugate. HUG-Br1 cDNA (2351 base pairs) and HUG-Br2 cDNA (2368 base pairs) encode proteins with 533 and 534 amino acid residues, respectively, with a typical membrane-insertion signal peptide, membrane-spanning domain, and 3 or 5 potential asparagine-linked glycosylation sites. At the nucleic acid and deduced amino acid sequence levels the two clones are 82% similar overall, 66% similar in the amino termini, and identical after codon 287, thus encoding proteins with the same carboxyl terminus. The mRNA encoding HUG-Br1 is of high abundance, and the one encoding HUG-Br2 is of low abundance; both are 2.6 kilobases in length. Both messages (2.6 kilobases) were present in the explanted liver of a Type I Crigler-Najjar patient, although the level for that of HUG-Br1 was reduced 4.5-fold. Northern blot analysis of poly(A)+ RNA isolated from the liver of an untreated and a phenobarbital-treated Erythrocebus patas monkey with 5'-specific probes for each clone indicated that the HUG-Br2-encoded message is induced two fold, but that for HUG-Br1 is not. These data indicate that bilirubin is glucuronidated by at least two different proteins, most likely present in very different amounts. These cDNAs which encode functional bilirubin UDP-Glucuronosyltransferases will allow the isolation of an appropriate gene to develop a gene therapy model for patients which have the totally deficient trait.
Peter I. Mackenzie - One of the best experts on this subject based on the ideXlab platform.
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transcriptional regulation of human udp Glucuronosyltransferase genes
Drug Metabolism Reviews, 2014Co-Authors: Robyn Meech, Ross A Mckinnon, Peter I. MackenzieAbstract:AbstractGlucuronidation is an important metabolic pathway for many small endogenous and exogenous lipophilic compounds, including bilirubin, steroid hormones, bile acids, carcinogens and therapeutic drugs. Glucuronidation is primarily catalyzed by the UDP-Glucuronosyltransferase (UGT) 1A and two subfamilies, including nine functional UGT1A enzymes (1A1, 1A3–1A10) and 10 functional UGT2 enzymes (2A1, 2A2, 2A3, 2B4, 2B7, 2B10, 2B11, 2B15, 2B17 and 2B28). Most UGTs are expressed in the liver and this expression relates to the major role of hepatic glucuronidation in systemic clearance of toxic lipophilic compounds. Hepatic glucuronidation activity protects the body from chemical insults and governs the therapeutic efficacy of drugs that are inactivated by UGTs. UGT mRNAs have also been detected in over 20 extrahepatic tissues with a unique complement of UGT mRNAs seen in almost every tissue. This extrahepatic glucuronidation activity helps to maintain homeostasis and hence regulates biological activity of en...
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The human UDP Glucuronosyltransferase, UGT1A10, glucuronidates mycophenolic acid.
Biochemical and biophysical research communications, 1997Co-Authors: B Mojarrabi, Peter I. MackenzieAbstract:The cDNA encoding the UDP Glucuronosyltransferase, UGT1A10, has been cloned from human colon. The deduced amino acid sequence of the cDNA is 90% similar in sequence to that of a previously characterized form, UGT1A9 (Hlug P4), and contains a signal peptide and carboxyl-terminal hydrophobic domain characteristic of all UDP Glucuronosyltransferases isolated to date. The enzyme synthesized in UGT1A10 cDNA-transfected COS-7 cells has a relative molecular mass of 56 kDa and is very active in the glucuronidation of mycophenolic acid (apparent Km of 34 microM and Vmax of 0.6 nmoles/min/mg protein). Other UGTs (UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 2B10 and 2B11) synthesized in COS cells had relatively little activity towards mycophenolic acid, suggesting that UGT1A10 may have a significant role in the elimination of this antineoplastic and immunosuppressive agent in vivo.
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Complementary deoxyribonucleic acid cloning and expression of a human liver uridine diphosphate-Glucuronosyltransferase glucuronidating carboxylic acid-containing drugs.
The Journal of pharmacology and experimental therapeutics, 1993Co-Authors: Chunjing Jin, John O Miners, K J Lillywhite, Peter I. MackenzieAbstract:A cDNA clone, designated UGT2B7 variant, encoding a 529-amino acid human liver microsomal uridine diphosphate-Glucuronosyltransferase (UGT) was isolated from a lambda gt11 human liver cDNA library. UGT2B7 variant synthesized in COS-7 cells was screened for activity toward a range of clinically used drugs and other xenobiotics. The expressed enzyme glucuronidated several carboxylic acid-containing nonsteroidal antiinflammatory agents including, in order of relative substrate activity, naproxen, ketoprofen, ibuprofen, fenoprofen, tiaprofenic acid, benoxprofen, zomepirac, diflunisal and indomethacin. Additionally, the stereoselectivity of ketoprofen, naproxen (S/R ratio approximately unity) and ibuprofen (S/R ratio 1.62) glucuronidation by the UGT2B7 variant was shown to differ. Two other carboxylic acid-containing drugs (clofibric acid and valproic acid) and a limited range of drugs containing an alcohol or phenolic functional group were also glucoronidated by expressed UGT2B7 variant. The deduced amino sequence of UGT2B7 variant was shown to differ only in one amino acid (tyrosine for histidine at position 268) from a previously published uridine diphosphate-Glucuronosyltransferase cDNA, UGT2B7. Like the previously reported enzyme, this variant efficiently glucuronidated hyodeoxycholic acid, estriol, 4-hydroxyestrone and 2-hydroxyestriol. It is, therefore, apparent that UGT2B7 variant has the capacity to glucuronidate with a degree of specificity both endogenous compounds and xenobiotics. Preferred substrates for UGT2B7 variant include xenobiotic carboxylic acids, polyhydroxylated estrogens and hyodeoxycholic acid.
Jayanta Roy Chowdhury - One of the best experts on this subject based on the ideXlab platform.
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kernicterus in an adult who is heterozygous for crigler najjar syndrome and homozygous for gilbert type genetic defect
Gastroenterology, 1997Co-Authors: Naga Chalasani, Jayanta Roy Chowdhury, Namita Roy Chowdhury, Thomas D BoyerAbstract:Gilbert syndrome is a common genetic disorder associated with mild unconjugated hyperbilirubinemia and no clinical illness. In contrast, Crigler-Najjar syndrome types I and II are rare genetic disorders associated with severe unconjugated hyperbilirubinemia and a life-long risk of kernicterus. Patients with Gilbert syndrome have low levels of a normal form of uridinediphosphoglucuronate Glucuronosyltransferase because of a defect in the promoter region of both alleles, whereas patients with Crigler-Najjar syndrome are homozygous for a defect that yields an abnormal form of the enzyme that has limited or no activity. This case report describes a young adult with Crigler-Najjar syndrome type II in whom kernicterus developed after a laparoscopic cholecystectomy. The development of kernicterus was the result of a largely preventable series of events that lead to an increase in the free fraction of his serum bilirubin. Analysis of his genetic defect showed that he was homozygous for the mutation associated with Gilbert syndrome and heterozygous for a second mutation in the open reading frame of one allele of the bilirubin uridinediphosphoglucuronate Glucuronosyltransferase gene. The combined defect leads to severe hyperbilirubinemia and shows how seemingly benign genetic defects, when combined, can cause serious clinical disease.
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the genetic basis of the reduced expression of bilirubin udp Glucuronosyltransferase 1 in gilbert s syndrome
The New England Journal of Medicine, 1995Co-Authors: Piter J. Bosma, Peter L. M. Jansen, Jayanta Roy Chowdhury, Conny T Bakker, Shailaja Gantla, Anita De Boer, Ben A Oostra, D Lindhout, Guido N J Tytgat, Ronald Oude P J ElferinkAbstract:Background People with Gilbert's syndrome have mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis. Hepatic glucuronidating activity, essential for efficient biliary excretion of bilirubin, is reduced to about 30 percent of normal. Methods We sequenced the coding and promoter regions of the gene for bilirubin UDP-Glucuronosyltransferase 1 (bilirubin/uridine diphosphoglucuronate-Glucuronosyltransferase 1) — the only enzyme that contributes substantially to bilirubin glucuronidation — in 10 unrelated patients with Gilbert's syndrome, 16 members of a kindred with a history of Crigler–Najjar syndrome type II, and 55 normal subjects. Results The coding region of the gene for the enzyme was normal in the 10 patients with Gilbert's syndrome. These patients were homozygous for two extra bases (TA) in the TATAA element of the 5' promoter region of the gene (A(TA)7TAA rather than the normal A(TA)6TAA). The presence of the longer TATAA element resulted in the reduced expr...
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The UDP Glucuronosyltransferase gene superfamily: Suggested nomenclature based on evolutionary divergence
DNA and Cell Biology, 1991Co-Authors: Brian Burchell, Karl W. Bock, Gerard J. Mulder, Takashi Iyanagi, Doron Lancet, Peter L. M. Jansen, Jayanta Roy Chowdhury, David R. Nelson, Gérard SiestAbstract:ABSTRACT A nomenclature system for the UDP Glucuronosyltransferase superfamily is proposed, based on divergent evolution of the genes. A total of 26 distinct cDNAs in five mammalian species have been sequenced to date. Comparison of the deduced amino acid sequences leads to the definition of two families and a total of three subfamilies. For naming each gene, we propose that the root symbol UGT for human (Ugt for mouse), representing "UDP Glucuronosyltransferase," be followed by an Arabic number denoting the family, a letter designating the subfamily, and an Arabic numeral representing the individual gene within the family or sub-family (hyphen before the Arabic number for mouse), e.g., human UGT2B1 and murine Ugt2b-1. Whereas the gene and cDNA should be italicized, the corresponding transcript, protein, and enzyme activity should not be written with lowercase letters or in italics, e.g., human or murine UGT2B1. Recent experimental evidence suggests that several exons of the UGT1 gene might be shared, ind...
Tsuyoshi Yokoi - One of the best experts on this subject based on the ideXlab platform.
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trans 3 hydroxycotinine o and n glucuronidations in human liver microsomes
Drug Metabolism and Disposition, 2005Co-Authors: Hiroyuki Yamanaka, Ayano Kanoh, Miki Katoh, Miki Nakajima, Hiroyuki Ishibashi, Osamu Tamura, Tsuyoshi YokoiAbstract:Trans -3′-hydroxycotinine is a major metabolite of nicotine in humans and is mainly excreted as O -glucuronide in smoker's urine. Incubation of human liver microsomes with UDP-glucuronic acid produces not only trans -3′-hydroxycotinine O -glucuronide but also N -glucuronide. The formation of N -glucuronide exceeds the formation of O -glucuronide in most human liver microsomes, although N -glucuronide has never been detected in human urine. Trans -3′-hydroxycotinine N -glucuronidation in human liver microsomes was significantly correlated with nicotine and cotinine N -glucuronidations, which are catalyzed mainly by UDP-Glucuronosyltransferase (UGT)1A4 and was inhibited by imipramine and nicotine, which are substrates of UGT1A4. Recombinant UGT1A4 exhibited substantial trans -3′-hydroxycotinine N -Glucuronosyltransferase activity. These results suggest that trans -3′-hydroxycotinine N -glucuronidation in human liver microsomes would be mainly catalyzed by UGT1A4. In the present study, trans -3′-hydroxycotinine O -glucuronidation in human liver microsomes was thoroughly characterized, since trans -3′-hydroxycotinine O -glucuronide is one of the major metabolites of nicotine. The kinetics were fitted to the Michaelis-Menten equation with a K m of 10.0 ± 0.8 mM and a V max of 85.8 ± 3.8 pmol/min/mg. Among 11 recombinant human UGT isoforms expressed in baculovirus-infected insect cells, UGT2B7 exhibited the highest trans -3′-hydroxycotinine O -Glucuronosyltransferase activity (1.1 pmol/min/mg) followed by UGT1A9 (0.3 pmol/min/mg), UGT2B15 (0.2 pmol/min/mg), and UGT2B4 (0.2 pmol/min/mg) at a substrate concentration of 1 mM. Trans -3′-hydroxycotinine O -Glucuronosyltransferase activity by recombinant UGT2B7 increased with an increase in the substrate concentration up to 16 mM (10.5 pmol/min/mg). The kinetics by recombinant UGT1A9 were fitted to the Michaelis-Menten equation with K m = 1.6 ± 0.1 mM and V max = 0.69 ± 0.02 pmol/min/mg of protein. Trans -3′-hydroxycotinine O -Glucuronosyltransferase activities in 13 human liver microsomes ranged from 2.4 to 12.6 pmol/min/mg and were significantly correlated with valproic acid glucuronidation ( r = 0.716, p < 0.01), which is catalyzed by UGT2B7, UGT1A6, and UGT1A9. Trans -3′-hydroxycotinine O -Glucuronosyltransferase activity in human liver microsomes was inhibited by imipramine (a substrate of UGT1A4, IC50 = 55 μM), androstanediol (a substrate of UGT2B15, IC50 = 169 μM), and propofol (a substrate of UGT1A9, IC50 = 296 μM). Interestingly, imipramine (IC50 = 45 μM), androstanediol (IC50 = 21 μM), and propofol (IC50 = 41 μM) also inhibited trans -3′-hydroxycotinine O -Glucuronosyltransferase activity by recombinant UGT2B7. These findings suggested that trans -3′-hydroxycotinine O -glucuronidation in human liver microsomes is catalyzed by mainly UGT2B7 and, to a minor extent, by UGT1A9.