Identification of Human UDP-Glucuronosyltransferase Isoform(s) Responsible for the Glucuronidation of 2-(4-Chlorophenyl)-5-(2-Furyl)-4-Oxazoleacetic Acid (TA-1801A)

Kaji, Hidefumi; Kume, Toshiyuki

doi:10.2133/dmpk.20.212

Cited by 9 publications

(6 citation statements)

References 21 publications

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“…Bilirubin (the preferred substrate of UGT1A1), hyodeoxycholic acid (the preferred substrate of UGT2B4 and 2B7), or zidovudine (the preferred substrate of UGT2B7) was added to the reaction mixture at final concentrations of 250 mM, 250 mM, and 1 mM, respectively. 14,15) The glucuronidation of Rand S-carvedilol in #18888, HH31, and also HH35 was inhibited significantly, but did not disappear completely even in the presence of high concentrations of the UGT substrates. In contrast, the glucuronidation of R-carvedilol in three kinds of HLM increased approximately 1.6-fold in the presence of 50 mM amiodarone, whereas that of S-carvedilol was increased only slightly by amiodarone.…”

Section: Resultsmentioning

confidence: 99%

“…We evaluated the effect of amiodarone (50 mM), desethylamiodarone (25 mM), bilirubin (250 mM), hyodeoxycholic acid (250 mM), and zidovudine (1 mM) on the glucuronidation of carvedilol. [13][14][15] Assay of Carvedilol Enantiomers The amount of carvedilol in the samples was measured using chiral high performance liquid chromatography (HPLC) as described by Saito et al with minor modifications. [7][8][9][10]16) Briefly, carvedilol was extracted from the samples (0.1 ml) with 5 ml diethylether after alkalization in 3 ml of 0.1 M Britton-Robinson buffer (pH 8.5).…”

Section: Methodsmentioning

confidence: 99%

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Inhibitory and Stimulative Effects of Amiodarone on Metabolism of Carvedilol in Human Liver Microsomes

Horiuchi

Kato

Nakamura

et al. 2010

Biological & Pharmaceutical Bulletin

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Carvedilol is a b-adrenoceptor antagonist that has been clinically used to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmia. 1) Orally administered carvedilol undergoes stereoselective first-pass metabolism, and the blood concentration of S-enantiomer with high b-blocking activity is approximately one-half of that of R-enantiomer with low b-blocking activity. 2,3) Both enantiomers are mostly eliminated by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose. 4) Carvedilol is metabolized extensively via aliphatic side-chain oxidation, aromatic ring oxidation, and conjugation pathways. 5) Oldham and Clarke reported that the oxidative metabolism of carvedilol is mediated by cytochrome P450 (CYP) 2D6, 2C9, 3A4, and 1A2 in microsomes from human lymphoblastoid cells expressing human CYP. 6) In addition, our previous findings indicated that R-carvedilol is metabolized mainly by CYP2D6 and partly by CYP1A2, 2C9, and 3A4, and that S-carvedilol is metabolized mainly by CYP1A2 and partly by CYP2C9, 2D6, and 3A4. 7-10) On the other hand, Ohno et al. found that uridine 5Ј-diphosphate (UDP)-glucuronosyltransferase (UGT) 2B7, 2B4, and 1A1 are capable of catalyzing the glucuronidation of carvedilol using microsomes from insect cells expressing human UGT. 11) In addition, they have demonstrated that glucuronidation of R-carvedilol is mediated by UGT1A1 and 2B4, and that glucuronidation of S-carvedilol is mediated by UGT2B7 and 2B4. 11) In 2005, Fukumoto et al. reported the effect of amiodarone on the stereoselective pharmacokinetics of carvedilol in patients with heart failure. 12) That is, they demonstrated that the mean serum concentration to dose (C/D) ratio of S-carvedilol in 54 patients who took amiodarone concomitantly with carvedilol was 2-fold higher than that in 52 patients who took carvedilol alone. On the other hand, there was no significant difference in the mean C/D values of R-carvedilol between the two groups. 12) They speculated that the oxidative metabolism of only S-carvedilol might be markedly inhibited by coadministration of amiodarone; however, the effects of amiodarone and/or its metabolite on the oxidation and glucuronidation of carvedilol enantiomers are still unresolved. 12) In the present study, to evaluate the mechanism responsible for the interaction between carvedilol and amiodarone, we investigated inhibitory and stimulative effects of amiodarone and desethylamiodarone on the metabolism of R-and S-carvedilol in human liver microsomes (HLM). The oxidation of carvedilol in HLM was evaluated in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH), whereas glucuronidation was evaluated in the presence of UDP-glucuronic acid (UDPGA). MATERIALS AND METHODS MaterialsCarvedilol was kindly supplied by Daiichi Sankyo Co., Ltd. (Tokyo, Japan). NADPH was obtained from Kohjin Co., Ltd. (Tokyo, Japan). UDPGA trisodium salt, amiodarone hydrochloride, furafylline, sulfaphenazole, and quinidine hydrochloride...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Inhibitory and Stimulative Effects of Amiodarone on Metabolism of Carvedilol in Human Liver Microsomes

Horiuchi

Kato

Nakamura

et al. 2010

Biological & Pharmaceutical Bulletin

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“…Human UGT1A3 expressed in HEK293 or Chinese hamster lung cells was shown to have activity toward catechol estrogens, several amine substrates, anthraquinones and chemopreventive flavonoids such as naringenin and quercetin (Cheng et al, 1998b;Green et al, 1998;Chen et al, 2005). Recently, the isozyme was found to catalyse the glucuronidation of an investigational anticancer agent, TA-1801A (Kaji and Kume, 2005). Thus, several UGT1A3 substrates play a role in carcinogenesis, chemoprevention and cancer therapy.…”

Section: Ugt1a3mentioning

confidence: 99%

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

2006

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The uridine diphosphoglucuronosyltransferases (UGTs) belong to a superfamily of enzymes that catalyse the glucuronidation of numerous endobiotics and xenobiotics. Several human hepatic and extrahepatic UGT isozymes have been characterized with respect to their substrate specificity, tissue expression and gene structure. Genetic polymorphisms have been identified for almost all the UGT family members. A wide variety of anticancer drugs, dietary chemopreventives and carcinogens are known to be conjugated by members of both UGT1A and UGT2B subfamilies. This review examines in detail each UGT isozyme known to be associated with cancer and carcinogenesis. The cancer-related substrates for several UGTs are summarized, and the functionally relevant genetic polymorphisms of UGTs are reviewed. A number of genotype-phenotype association studies have been carried out to characterize the role of UGT pharmacogenetics in several types of cancer, and these examples are discussed here. In summary, this review focuses on the role of the human UGT genetic polymorphisms in carcinogenesis, chemoprevention and cancer risk.

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“…Ethynylestradiol and tranilast are the substrates of UGT1A1 (McGinnity et al, 2004;Katoh et al, 2007). Propofol, a substrate of UGT1A9, has been reported to inhibit UGT1A1 activities (Williams et al, 2004;Kaji and Kume, 2005). Therefore, they could potently inhibit the estradiol 3-O-glucuronide formation in both human liver microsomes and recombinant UGT1A1.…”

Section: Comparison Of the Inhibitory Effects Of A Variety Of Compounmentioning

confidence: 99%

Product Inhibition of UDP-Glucuronosyltransferase (UGT) Enzymes by UDP Obfuscates the Inhibitory Effects of UGT Substrates

Fujiwara

Nakajima²,

Yamanaka³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Substrates that are specific for certain UDP-glucuronosyltransferase (UGT) isoforms are usually used as specific inhibitors to identify UGT isoforms responsible for the glucuronidation of drugs. 1-Naphthol and 4-nitrophenol are probe substrates for human UGT1A6. In the present study, we found that UGT1A1-catalyzed estradiol 3-O-glucuronide formation and UGT1A4-catalyzed imipramine N-glucuronide formation in human liver microsomes were prominently decreased in the presence of 1-naphthol, but those by recombinant human UGT1A1 and UGT1A4, respectively, were not. Interestingly, when recombinant UGT1A6 was added in the reaction mixture, these activities by recombinant UGT1A1 and UGT1A4 were diminished in the presence of 1-naphthol. To interpret this phenomenon, the inhibitory effects of 1-naphthol O-glucuronide and UDP, products of the glucuronidation of 1-naphthol, were investigated. We found that UDP strongly inhibited the UGT1A1 (K i ‫؍‬ 7 M) and UGT1A4 (K i ‫؍‬ 47 M) activities in a competitive manner for the 5-diphosphoglucuronic acid binding. These results suggest that UDP produced by UGT1A6-catalyzed 1-naphthol glucuronidation, but not 1-naphthol O-glucuronide and 1-naphthol per se, is the actual inhibition substance. Next, we examined the inhibitory effects of 15 compounds that are substrates of UGTs on estradiol 3-O-glucuronide formation in human liver microsomes compared with those by recombinant UGT1A1. Among them, 4 compounds (1-naphthol, 2-naphthol, 4-nitrophenol, and 4-methylumbelliferone) with high turnover rates (V max /K m value >200 l/ min/mg) showed more potent inhibition of the activity in human liver microsomes compared with that by the recombinant UGT1A1. Thus, we should pay attention to the inhibitory effects of UDP on UGT, which may cause erroneous evaluations in inhibition studies using human liver microsomes.UDP-glucuronosyltransferases (UGTs) are a superfamily of enzymes that catalyze the formation of glucuronides by the transfer of glucuronic acid from a cofactor uridine 5Ј-diphosphoglucuronic acid (UDPGA) to hydroxyl, carboxyl, or amine groups of endogenous and exogenous substrates (Dutton, 1980). The hydrophilic glucuronides can readily be excreted from the body via bile and urine. Human UGTs are classified into two subfamilies, UGT1 and UGT2, based on similarities between their amino acid sequences and gene organization (Mackenzie et al., 2005). To date, 19 human UGT isoforms, UGT1A1, -1A3, -1A4, -1A5, -1A6, -1A7, -1A8, -1A9, -1A10, -2A1, -2A2, -2A3, -2B4, -2B7, -2B10, -2B11, -2B15, -2B17, and -2B28, have been identified (Mackenzie et al., 2005). Most UGT enzymes are expressed in liver, but some isoforms such as UGT1A7, -1A8, and -1A10 are exclusively expressed in intestine Burchell et al., 2001).Most pharmacokinetic drug-drug interactions occur at the metabolic level and usually involve changes in the activity of the major drug-metabolizing enzymes such as UGT. Identification of the UGT(s) involved in the metabolism of a given compound allows us to predict potential drug-drug ...

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Identification of Human UDP-Glucuronosyltransferase Isoform(s) Responsible for the Glucuronidation of 2-(4-Chlorophenyl)-5-(2-Furyl)-4-Oxazoleacetic Acid (TA-1801A)

Cited by 9 publications

References 21 publications

Inhibitory and Stimulative Effects of Amiodarone on Metabolism of Carvedilol in Human Liver Microsomes

Inhibitory and Stimulative Effects of Amiodarone on Metabolism of Carvedilol in Human Liver Microsomes

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

Product Inhibition of UDP-Glucuronosyltransferase (UGT) Enzymes by UDP Obfuscates the Inhibitory Effects of UGT Substrates

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