Genetic Variation of Human UDP-Glucuronosyltransferase

Burchell, Brian

doi:10.2165/00129785-200303010-00006

Cited by 90 publications

(30 citation statements)

References 123 publications

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“…Expression is triggered by processes associated with birth and activity reaches adult levels by 3 to 6 months postnatal age (Burchell et al, 1989). In contrast, UGT1A3 activity is present in the fetal and neonatal liver at levels 30% of those observed in the adult (Burchell et al, 1989). This observation would suggest a developmental expression pattern including a postneonatal increase in expression, but this remains to be elucidated.…”

Section: Udp-glucuronosyltransferasementioning

confidence: 93%

“…UGT1A1, the enzyme most active toward bilirubin, is absent from the fetal liver. Expression is triggered by processes associated with birth and activity reaches adult levels by 3 to 6 months postnatal age (Burchell et al, 1989). In contrast, UGT1A3 activity is present in the fetal and neonatal liver at levels 30% of those observed in the adult (Burchell et al, 1989).…”

Section: Udp-glucuronosyltransferasementioning

confidence: 99%

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The Ontogeny of Human Drug-Metabolizing Enzymes: Phase II Conjugation Enzymes and Regulatory Mechanisms: Table 1

McCarver¹,

Hines²

2002

J Pharmacol Exp Ther

320

151

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Changes in phase II drug-metabolizing enzyme expression during development, as well as the balance between phase I and phase II enzymes, can significantly alter the pharmacokinetics for a given drug or toxicant. Although our knowledge is incomplete, many of the phase II enzymes are expressed early in development. There is evidence for glutathione S-transferase A1/A2 (GSTA1/A2), GSTM, and GSTP1 in fetal liver, lung and kidney, although tissue-specific patterns and changes with time are observed. N-Acetyltransferase 1 (NAT1) activity also has been reported throughout gestation in fetal liver, adrenal glands, lung, kidney, and intestine. Only postnatal changes in NAT1 expression were apparent. Nothing is known about human NAT2 developmental expression. Some UDP-glucuronosyltransferase and sulfotransferase isoforms also are detectable in fetal liver and other tissues by the first or second trimester, and substantial changes in isoform expression patterns, as well as overall expression levels, are observed with increasing maturity. Finally, expression of both epoxide hydrolases 1 and 2 (EPHX1 and EPHX2) is observed in fetal liver, and for the former, increased expression with time has been documented. Less is known about ontogenic molecular control mechanisms. Limited data suggest that the hepatocyte nuclear factor and CCAAT/enhancer binding protein families are critical for fetal liver drug-metabolizing enzyme expression whereas D element binding protein and related factors may regulate postnatal hepatic expression. There is a paucity of data regarding mechanisms for the onset of extrahepatic fetal expression or specific mechanisms determining temporal switches, such as those observed within the CYP3A and flavin-containing monooxygenase families.Taking advantage of electrophilic functional groups already present on the molecule, or ones introduced during phase I metabolism, the phase II drug-metabolizing enzymes (DMEs) are characterized by their ability to conjugate xenobiotics using small molecular weight, organic donor molecules such as glutathione, UDP-glucuronic acid, or acetyl coenzyme A. These reactions generally result in pharmacological inactivation or detoxification, although instances of bioactivation are known. Conjugation products also can be substrates for specific transport enzymes, thus facilitating elimination from the body. Historically, research on DMEs has placed more emphasis on those catalyzing phase I versus phase II reactions. This also has been true with respect to studies on DME developmental expression. Given the importance of the conjugation enzymes in drug and toxicant disposition and, in particular, how the balance between phase I and phase II enzymes can dramatically alter pharmacokinetics and therefore therapeutic efficacy and/or xenobiotic toxicity, this area deserves increased attention.Advances in our understanding of phase II enzyme expression during ontogeny have been hampered by many of the same problems discussed for the phase I enzymes (Hines and McCarver, 2002). These ...

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Section: Udp-glucuronosyltransferasementioning

confidence: 93%

Section: Udp-glucuronosyltransferasementioning

confidence: 99%

The Ontogeny of Human Drug-Metabolizing Enzymes: Phase II Conjugation Enzymes and Regulatory Mechanisms: Table 1

McCarver¹,

Hines²

2002

J Pharmacol Exp Ther

320

151

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“…The UGTs catalyse the transfer of the glucuronic acid moiety from the co-substrate UDP-glucuronic acid to the substrate, resulting in a metabolite with greater polarity and water solubility. Several UGT isozymes exist, and 18 human liver cDNAs have been cloned to date (Burchell, 2003). Genetic polymorphisms are known to exist in human UGT genes, and various studies have examined the role of this genetic variation in the glucuronidation of carcinogens as well as anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

“…The effect of UGT polymorphisms on the prevalence rates of various types of cancer has also been studied. The substrate specificity, tissue-specific expression and relevance in different disease states of the UGT isozymes have been reviewed elsewhere (Burchell and Coughtrie, 1989;Miners and Mackenzie, 1991;Tukey and Strassburg, 2000;Burchell, 2003;Wells et al, 2004). With new polymorphisms being frequently discovered in UGT genes, this chapter aims at providing an updated and comprehensive review of genetic variation in the UGT gene family, and its relevance to cancer.…”

Section: Introductionmentioning

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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“…Since glucuronidation plays an important role in drug metabolism, genetic variation in UGT genes is likely to have significant impact on pharmacokinetics of drugs that are mainly metabolized by UGTs [141]. In addition, genetic variation in UGT genes is likely to have some physiological consequences, because the UGTs also participate in the homeostasis of a number of endogenous substances [142].…”

Section: Udp-glucuronosyltransferases (Ugts)mentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Variability: A Daunting Challenge in Drug Therapy

Lin¹

2007

CDM

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Patients vary considerably in their response to drug therapy. A drug that proves to be pharmacologically effective in some patients at a given dose may be ineffective or even toxic in others. The interindividual variability in drug response represents a major challenge in drug therapy, particularly for drugs with narrow therapeutic index. The intensity and duration of a drug action are determined not only by pharmacokinetic processes, but also by pharmacodynamic processes. Therefore, the variability in drug response is a result of the variability in either pharmacokinetic or pharmacodynamic processes, or a combination of both. The purpose of this paper is to review the sources that contribute to pharmacokinetic and pharmacodynamic variability. Although the main focus will be on the genetic variability, the impact of environmental factors on drug response will also be discussed. Finally, the application and limitation of the concept of personalized medicine will be briefly discussed.

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Genetic Variation of Human UDP-Glucuronosyltransferase

Cited by 90 publications

References 123 publications

The Ontogeny of Human Drug-Metabolizing Enzymes: Phase II Conjugation Enzymes and Regulatory Mechanisms: Table 1

The Ontogeny of Human Drug-Metabolizing Enzymes: Phase II Conjugation Enzymes and Regulatory Mechanisms: Table 1

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

Pharmacokinetic and Pharmacodynamic Variability: A Daunting Challenge in Drug Therapy

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