Glucuronidation of Drugs and Drug-Induced Toxicity in Humanized<i>UDP-Glucuronosyltransferase 1</i>Mice

Kutsuno, Yuki; Itoh, Tomoo; Tukey, Robert H.; Fujiwara, Ryoichi

doi:10.1124/dmd.114.057083

Cited by 25 publications

(17 citation statements)

References 42 publications

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“…Similarly, clearances of S -naproxen and ibuprofen O -glucuronidations in mouse liver microsomes are approximately 3-fold greater than those in human liver microsomes [44]. In contrast, the clearance value of etodolac O -glucuronidation in mouse liver microsomes is 3-fold lower than that in human liver microsomes [45]. These differences in the clearance parameters are mainly attributed to different K m and V max values between the species.…”

Section: Species Differences In the Expression And Function Of Udpmentioning

confidence: 99%

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Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans

Fujiwara

Yoda

Tukey

2018

Drug Metabolism and Pharmacokinetics

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More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic. Animals such as mice and rats are widely used to predict drug metabolism and drug-induced toxicity in humans. However, there are marked species differences in the expression and function of drug-metabolizing enzymes including UGTs. To overcome the species differences, mice in which certain drug-metabolizing enzymes are humanized have been recently developed. Humanized UGT1 (hUGT1) mice were created in 2010 by crossing Ugt1-null mice with human UGT1 transgenic mice in a C57BL/6 background. hUGT1 mice can be promising tools to predict human drug glucuronidation and acyl-glucuronide-associated toxicity. In this review article, studies of drug metabolism and toxicity in the hUGT1 mice are summarized. We further discuss research and strategic directions to advance the understanding of drug glucuronidation in humans.

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Section: Species Differences In the Expression And Function Of Udpmentioning

confidence: 99%

“…In the ibuprofen O -glucuronidation, human liver microsomes exhibit a higher K m value. Meanwhile, human liver microsomes show lower K m values in etodolac and diclofenac O -glucuronidations [45]. …”

Section: Species Differences In the Expression And Function Of Udpmentioning

confidence: 99%

Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans

Fujiwara

Yoda

Tukey

2018

Drug Metabolism and Pharmacokinetics

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“…Diclofenac glucuronidation by recombinant UGTs (UGT1A3, UGT1A9, UGT2B7, and UGT2B17), HLMs, and HIMs was examined according to a method reported previously (Kutsuno et al, 2014), with slight modifications. Briefly, a typical incubation mixture (200 ml of total volume) contained 100 mM phosphate buffer (pH 7.4), 4 mM MgCl 2 , 5 mM UDPGA, 50 mg/ml alamethicin, 0.1 mg/ml HLM or HIM, 0.5-50 mM zafirlukast, and diclofenac.…”

Section: Methodsmentioning

confidence: 99%

“…Detection was accomplished with a fluorescence detector at 276 nm for excitation and 667 nm for emission. Quantification of etodolac glucuronide was performed as described previously (Kutsuno et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

Targeted Screen for Human UDP-Glucuronosyltransferases Inhibitors and the Evaluation of Potential Drug-Drug Interactions with Zafirlukast

et al. 2015

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Inhibition of drug metabolizing enzymes is a major mechanism in drug-drug interactions (DDIs). A number of cases of DDIs via inhibition of UDP-glucuronosyltranseferases (UGTs) have been reported, although the changes in pharmacokinetics are relatively small in comparison with drugs that are metabolized by cytochrome P450s. Most of the past studies have investigated hepatic UGTs, although recent studies have revealed a significant contribution of UGTs in the small intestine to drug clearance. To evaluate potential DDIs caused by inhibition of intestinal UGTs, we assessed inhibitory effects of 578 compounds, including drugs, xenobiotics, and endobiotics, on human UGT1A8 and UGT1A10, which are major contributors to intestinal glucuronidation. We identified 29 inhibitors by monitoring raloxifene glucuronidation with recombinant UGTs. All of the inhibitors potently inhibited UGT1A1 activity, as well. We found that zafirlukast is a potent general inhibitor of UGT1As and a moderate inhibitor of UGT2Bs because it monitors 4-methylumbelliferone glucuronidation by recombinant UGTs. However, zafirlukast did not potently inhibit diclofenac glucuronidation, suggesting that the inhibitory effects might be substrate specific. Inhibitory effects of zafirlukast on some UGT substrates were further investigated in human liver and human small intestine microsomes in order to evaluate potential DDIs. The R values (the ratios of intrinsic clearance with and without an inhibitor) revealed that zafirlukast has potential to cause clinical DDIs in the small intestine. Although we could not identify specific UGT1A8 and UGT1A10 inhibitors, zafirlukast was identified as a general inhibitor for UGTs in vitro. The present study suggests that the inhibition of UGT in the small intestine would be an underlying mechanism for DDIs.

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“…Recently, humanized UGT1 mice (hUGT1 mice) in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus have been developed (Fujiwara et al, 2010(Fujiwara et al, , 2012. As UGT1A expression patterns in the liver and small intestine of hUGT1 mice were similar to those of humans (Nakamura et al, 2008;Fujiwara et al, 2010), hUGT1 mice have been used to evaluate pharmacological and toxicological species differences in UGTs (Kutsuno et al, 2013(Kutsuno et al, , 2014. Therefore, in this study, the expression pattern of UGT1As in brains from humans and hUGT1 mice was examined.…”

Section: Introductionmentioning

confidence: 99%

Expression ofUDP-Glucuronosyltransferase 1(UGT1) and Glucuronidation Activity toward Endogenous Substances in HumanizedUGT1Mouse Brain

et al. 2015

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Although UDP-glucuronosyltransferases (UGTs) are important phase II drug-metabolizing enzymes, they are also involved in the metabolism of endogenous compounds. Certain substrates of UGTs, such as serotonin and estradiol, play important roles in the brain. However, the expression of UGTs in the human brain has not been fully clarified. Recently, humanized UGT1 mice (hUGT1 mice) in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus have been developed. In the present study, the expression pattern of UGT1As in brains from humans and hUGT1 mice was examined. We found that UGT1A1, 1A3, 1A6, and 1A10 were expressed in human brains. The expression pattern of UGT1As in hUGT1 mouse brains was similar to that in human brains. In addition, we examined the expression of UGT1A1 and 1A6 in the cerebellum, olfactory bulbs, midbrain, hippocampus, and cerebral cortex of hUGT1 mice. UGT1A1 in all brain regions and UGT1A6 in the cerebellum and cerebral cortex of 6-month-old hUGT1 mice were expressed at a significantly higher rate than those of 2-week-old hUGT1 mice. A difference in expression levels between brain regions was also observed. Brain microsomes exhibited glucuronidation activities toward estradiol and serotonin, with mean values of 0.13 and 5.17 pmol/min/mg, respectively. In conclusion, UGT1A1 and UGT1A6 might play an important role in function regulation of endogenous compounds in a regionand age-dependent manner. Humanized UGT1 mice might be useful to study the importance of brain UGTs in vivo.

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Glucuronidation of Drugs and Drug-Induced Toxicity in HumanizedUDP-Glucuronosyltransferase 1Mice

Cited by 25 publications

References 42 publications

Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans

Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans

Targeted Screen for Human UDP-Glucuronosyltransferases Inhibitors and the Evaluation of Potential Drug-Drug Interactions with Zafirlukast

Expression ofUDP-Glucuronosyltransferase 1(UGT1) and Glucuronidation Activity toward Endogenous Substances in HumanizedUGT1Mouse Brain

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