UDP-glucuronosyltransferases and clinical drug-drug interactions

Kiang, Tony K. L.; Ensom, Mary H H; Chang, Thomas K. H.

doi:10.1016/j.pharmthera.2004.10.013

Cited by 505 publications

(382 citation statements)

References 155 publications

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“…The UGT1 subfamily of enzymes catalyses the glucuronidation of bilirubin and xenobiotic amines and phenols. A large number of xenobiotics is conjugated by the UGT1A isozymes, and some pharmacologically relevant substrates include analgesics, sex hormones, anticancer drugs like irinotecan and flavopiridol, and tobacco-specific carcinogens including polycyclic aromatic hydrocarbons and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) (Kiang et al, 2005).…”

Section: The Ugt Superfamilymentioning

confidence: 99%

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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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Section: The Ugt Superfamilymentioning

confidence: 99%

“…The UGT2B family members include UGT2B4, 2B7, 2B10, 2B11, 2B15, 2B17 and 2B28, along with some recently discovered pseudogenes (Riedy et al, 2000). These subfamily members catalyse the glucuronidation of bile acids, steroids and several therapeutic drugs (Kiang et al, 2005).…”

Section: The Ugt Superfamilymentioning

confidence: 99%

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

2006

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“…16 Glucuronides are charged at physiological pH values which hinders their diffusion across the lipid bilayer of cells, 17,18 effectively sequestering the glucuronide probe from contact with lysosomal bG. Conjugation of glucuronide moieties to xenobiotics by UDP-glucuronosyl transferases is also a major detoxification pathway in rodents and humans, 19 suggesting that a glucuronide probe should be resistant to premature activation by endogenous bG under physiological conditions.…”

Section: Introductionmentioning

confidence: 99%

Gene expression imaging by enzymatic catalysis of a fluorescent probe via membrane-anchored β-glucuronidase

Chuang

Wang

et al. 2007

Gene Ther

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Development of nonimmunogenic and specific reporter genes to monitor gene expression in vivo is important for the optimization of gene therapy protocols. We developed a membrane-anchored form of mouse b-glucuronidase (mbG) as a reporter gene to hydrolyze a nonfluorescent glucuronide probe (fluorescein di-b-D-glucuronide, (FDGlcU) to a highly fluorescent reporter to assess the location and persistence of gene expression. A functional b-glucuronidase (bG) was stably expressed on the surface of murine CT26 colon adenocarcinoma cells where it selectively hydrolyzed the cell-impermeable FDGlcU probe. FDGlcU was also preferentially converted to fluorescent probe by (bG) on CT26 tumors. The fluorescent intensity in bG-expressing CT26 tumors was 240 times greater than the intensity in control tumors. Selective imaging of gene expression was also observed after intratumoral injection of adenoviral bG vector into carcinoma xenografts. Importantly, mbG did not induce an antibody response after hydrodynamic plasmid immunization of Balb/c mice, indicating that the reporter gene product displayed low immunogenicity. A membraneanchored form of human bG also allowed in vivo imaging, demonstrating that human bG can be employed for imaging. This imaging system therefore, displays good selectivity with low immunogenicity and may help assess the location, magnitude and duration of gene expression in living animals and humans.

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“…Patient response to therapy is highly variable in part because defective alleles of UGT1A1 impair glucuronidation of SN-38 leading to its accumulation and resultant toxicity, including diarrhea and leucopenia [45,46] . Individuals who carry the variant UGT1A1 * 28 allele, which has a (TA) insertion in the UGT1A1 promoter region, TA 7 repeats instead of more common TA 6 repeats, have a decreased capacity to glucuronidate SN-38 [47] . Up to 33% of Caucasians carry the UGT1A1 * 28 variant [48] , and the US Food and Drug Administration has recommended a dose reduction for irinotecan in individuals who are homozygous for the UGT1A1 * 28 allele.…”

Section: Uridine Diphosphate Glucoronosyltransferasesmentioning

confidence: 99%

“…Up to 33% of Caucasians carry the UGT1A1 * 28 variant [48] , and the US Food and Drug Administration has recommended a dose reduction for irinotecan in individuals who are homozygous for the UGT1A1 * 28 allele. Apart from irinotecan/SN-38, UGT1A1 * 28 is also associated with decreased paracetamol, lamotrigine, lorazepam, and josamycin metabolism, but the pharmacokinetic and pharmacodynamic consequences of variant alleles have not been evaluated to date [47] .…”

Section: Uridine Diphosphate Glucoronosyltransferasesmentioning

confidence: 99%

Pharmacogenetics of drug-metabolizing enzymes in Italian populations

Serpe

Canaparo

Scordo

et al. 2014

Drug Metabolism and Personalized Therapy

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: Drug-metabolizing enzymes play a major role in the biotransformation and subsequent elimination of most drugs and xenobiotics from the body. Both phase I and phase II enzymes are highly polymorphic. Inter-individual differences in genes coding for drug-metabolizing enzymes are important for understanding variability in drug response and for individualization of drug prescription. The prevalence of genetic polymorphisms in drug metabolism varies widely with ethnicity, and marked differences in the distribution of allelic variants of genes encoding drug-metabolizing enzymes have been documented in populations of different racial origin. This review aimed to summarize the available studies on genetic polymorphisms associated with drug metabolism conducted in Italian populations and to compare the frequency of the various metabolizer phenotypes and most common variant alleles (and resulting genotypes) with corresponding values from other populations. Notably, published data are not extensive, and most studies were performed on relatively low numbers of individuals. In general, the frequency of polymorphisms in the cytochrome P450 ( CYP ) genes as well as in the investigated phase II enzymes in the Italian population was similar to values reported for other Caucasian populations. However, the prevalence of CYP2D6 gene duplication among Italians was found to be very high, confirming the higher frequency of CYP2D6 ultrarapid metabolizers in the Mediterranean area compared to Northern Europe. It is worth noting that a geographic gradient in the flavin-containing monooxygenase 3 polymorphism distribution was also seen, the Italian population showing higher similarity to other Mediterranean populations than to North Europeans.

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UDP-glucuronosyltransferases and clinical drug-drug interactions

Cited by 505 publications

References 155 publications

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

Gene expression imaging by enzymatic catalysis of a fluorescent probe via membrane-anchored β-glucuronidase

Pharmacogenetics of drug-metabolizing enzymes in Italian populations

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