Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system

Court, Michael H.

doi:10.3109/03602530903209288

Cited by 182 publications

(158 citation statements)

References 89 publications

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“…Because many factors can affect UGT2B7 activity, the activity of this enzyme displays large individual variability, 21 which further results in that human liver microsomal DES glucuronidation activity displays significant individual differences with DES glucuronidation activity ranging from 0.01 to 3.0 nmol/min/mg ( Figure 7). This suggests that the toxicity may correspondingly exhibit large individual variability in UGT2B7 activity-dependent manner.…”

Section: ■ Discussionmentioning

confidence: 99%

“…20 Many factors, such as polymorphism, age, and coadministrated compounds, can influence the activities of UGTs, which are often in isoformdependent manners. 21 Therefore, characterization of the UGTs responsible for glucuronidation of a toxicant is essential to understand the factors affecting the toxicities and to predict individual differences of potential toxicities.…”

Section: ■ Introductionmentioning

confidence: 99%

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Characterization of UDP-Glucuronosyltransferases Involved in Glucuronidation of Diethylstilbestrol in Human Liver and Intestine

Zhu

Liu

et al. 2012

Chem. Res. Toxicol.

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Diethylstilbestrol (DES), a synthetic estrogen, is famous for its carcinogenic effects. Human exposure to this compound can occur frequently through dietary ingestion and medical treatment. Glucuronidation has been demonstrated to be a predominant metabolic pathway for DES in human. Therefore, glucuronidation metabolism may have a significant impact on its toxicities, and it is essential to clarify this metabolic pathway. Accordingly, this in vitro study is designed to characterize the UGTs involved in DES glucuronidation and, furthermore, to identify the roles of individual isoforms in the reaction in liver and intestine. Human liver microsomes (HLM) displayed much higher potential for DES glucuronidation than human intestinal microsomes (HIM). The intrinsic clearances in HLM and HIM were demonstrated to be 459 and 14 μL/min/mg protein, respectively. Assays with recombinant UGTs demonstrated that UGT1A1, -1A3, -1A8, and -2B7 could catalyze DES glucuronidation, among which UGT2B7 showed the highest affinity. Chemical inhibitors of UGT2B7 and UGT1A1/1A3 both displayed similar inhibition against the reaction in UGT2B7 and HLM. In addition, DES glucuronidation in individual HLM exhibited a large individual variability and strongly correlated to UGT2B7 activity. All evidence indicates that UGT2B7 may act as a major enzyme responsible for DES glucuronidation in human liver. For HIM, both UGT2B7 inhibitor and UGT1A1/1A3/1A8 inhibitor exerted moderate inhibition. It is suggested that although UGT2B7 contributes to DES glucuronidation in intestine, other UGTs may contribute equally. In summary, this study characterizes human UGTs involved in DES glucuronidation in human liver and intestine, which may be helpful for further study about DES-related toxicities. Figure 1), a synthetic nonsteroid estrogen, is famous for its carcinogenicity. Human exposure to this compound can occur directly or indirectly through dietary ingestion and medical treatment. 1−4 DES was once prescribed widely to millions of pregnant women in false hopes of preventing miscarriage and other pregnancy complications in the United States. 1 It is now still accepted as an efficient therapy for the treatment of prostate and breast cancers. 2,3 Aside from its wide clinical applications, DES has found widespread application as a growth promoter in feeding cattle, sheep, and poultry. 4 It was estimated that in 1971 alone as much as 27600 kg of DES was used in livestock feeding in the United States. 5 After widespread and extensive exposures to DES, numerous serious health problems have been encountered. DES was established to cause the rare clear cell adenocarcinoma (CCAC) of the vagina and cervix in "DES daughters" (who are exposed to DES before birth). 6 In addition to CCAC, these daughters were found to suffer from malformations of their genital tracts, which can result in severe pregnancy and fertility problems. 7−9 Just like DES daughters, DES sons were also found to be prone to DES damage in the genitalia. 10 In company with daughters and so...

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Section: ■ Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Characterization of UDP-Glucuronosyltransferases Involved in Glucuronidation of Diethylstilbestrol in Human Liver and Intestine

Zhu

Liu

et al. 2012

Chem. Res. Toxicol.

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“…Interestingly, expression of human hepatic UGT2 members (UGT2B4, 2B7, 2B10, 2B15 and 2B17) is in general higher than that of family 1 members [56,57]. UGT2 members are known to be involved in catabolism of steroids and bile acids.…”

Section: Species Differences Of Rat and Human Hepatic Ugt Induction Bmentioning

confidence: 99%

“…Studies of human liver banks revealed large interindividual variation of UGT activities [56]. However, underlying factors (LATFs, liver-enriched transcription factors as well as genetic diversity [64]) are difficult to distinguish.…”

Section: Species Differences Of Rat and Human Hepatic Ugt Induction Bmentioning

confidence: 99%

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From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Bock¹

2011

Biochemical Pharmacology

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. From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans. Biochemical Pharmacology, Elsevier, 2011, 82 (1) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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Clinical Aspects of Drug Biotransformation: An OverviewDedicated to the memory of Mark J. Winn, Ph.D.,1960–1993

Coleman

Radulovic

2012

Encyclopedia of Drug Metabolism and Interactions

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The success of a new drug largely depends on the lessons learned from both existing successful and unsuccessful drugs. Although there are many factors that govern the overall effectiveness of a particular agent, its presence for a period commensurate with optimum efficacy is essential at the receptor or tissue and this is governed by clearance. In turn, clearance depends on the myriad processes of biotransformation, which have evolved to serve the individual through biosynthesis and disposal of vital small molecules. Biotransformation is also tasked with protecting homeostasis from xenobiotic agents by removing them, usually through varying degrees of structural alteration aimed at increasing water solubility that promotes renal excretion. This chapter is intended to provide an overview of the major oxidative, conjugative, and hydrolyzing capabilities of our biotransforming enzyme systems, alongside their impressively flexible and highly adapted means of detecting and monitoring small molecules to be metabolized. The role of biotransformation in the insurance of population survival through genetic enzymatic polymorphisms is also explored and its impact on the individual's treatment experience. The effect on biotransformation of inhibition is discussed, as are the major factors the patient brings to the drug treatment process, such as age, disease, gender, and pregnancy. Finally, how the process of drug discovery accommodates biotransformation is outlined from the perspective of the pharmaceutical industry. Understanding of all these interlocking and complex processes will provide an insight into how mass drug therapy can be harnessed to minimize toxicity and maximize efficacy in the twenty‐first century.

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Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system

Cited by 182 publications

References 89 publications

Characterization of UDP-Glucuronosyltransferases Involved in Glucuronidation of Diethylstilbestrol in Human Liver and Intestine

Characterization of UDP-Glucuronosyltransferases Involved in Glucuronidation of Diethylstilbestrol in Human Liver and Intestine

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Clinical Aspects of Drug Biotransformation: An OverviewDedicated to the memory of Mark J. Winn, Ph.D.,1960–1993

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