Polymorphisms and Haplotypes of the UDP-Glucuronosyltransferase 2B7 Gene Promoter

Hu, Dong; Meech, Robyn; Lu, Lu; Mackenzie, Peter I.

doi:10.1124/dmd.113.056630

Cited by 21 publications

(20 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Precise data on the frequency of this polymorphism in the UK population were not available from the literature or 1000 genomes, possibly due to the nature of the polymorphism. UGT2B7 is one of the more important drug metabolizing UGTs, and a nonsynonymous polymorphism (rs7439366) in this gene has been quite well studied and appears to affect enzyme activity, either directly by increased enzyme activity [48] or more indirectly due to strong linkage disequilibrium with an upstream sequence showing higher levels of transcription [49] . As summarized in Table 2 , the rs7439366 variant appears slightly more common in the UK than in Spanish or Finnish individuals on the basis of 1000 genomes with the UK estimate in good agreement with published data on UK controls [26] .…”

Section: Udp-glucuronosyltransferase Polymorphismsmentioning

confidence: 99%

Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: review of current knowledge and comparison with selected European populations

Daly

2015

Drug Metabolism and Personalized Therapy

View full text Add to dashboard Cite

Data on frequency of pharmacogenetic polymorphisms in the UK population are limited. However, availability of whole genome sequencing data on 94 UK controls of European ethnicity from the 1000 genomes project together with similar data on other populations provides a valuable new source of data in this area and allows direct comparison of allele frequencies with those for other European populations. The ethnic diversity of the UK population also needs to be considered, and 1000 genomes includes data on South Asians, the most common ethnic group in the UK after White Europeans. Allele frequencies for polymorphisms in genes relevant to phase I and phase II drug metabolism for UK, Finnish, Spanish and South Asian populations were obtained from the literature and 1000 genomes. Generally there was good agreement between the literature and 1000 genomes reports. CYP2D6*4, the most common CYP2D6 poor metabolizer allele among Europeans, appears more common in the UK than in Spain and Finland, whereas, as suggested previously, CYP2C19*2 and CYP2C9*2 appear more common in Finland and Spain, respectively, than in the UK. South Asians show low frequencies of CYP2C9*2 and CYP2C19*17 but higher frequencies of CYP2C19*2 compared with UK residents of European ethnicity. Though personalizing drug treatment on the basis of individual genotype rather than ethnicity may be more appropriate, differences in allele frequencies across continents should be considered when designing clinical trials of new drugs.

show abstract

Section: Udp-glucuronosyltransferase Polymorphismsmentioning

confidence: 99%

Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: review of current knowledge and comparison with selected European populations

Daly

2015

Drug Metabolism and Personalized Therapy

View full text Add to dashboard Cite

show abstract

“…Most studies on UGT2B7 genetic variants focused on the *2 (802C>T; His268Tyr; rs7439366) allele highly prevalent in the Caucasian population (~0.50), which has, however, little impact on substrate selectivity and activity. Two other major haplotypes in the proximal promoter of the UGT2B7 gene (–138A>G, rs7668258, and −900A>G, rs7438135) may be further modulated by the presence of rare polymorphisms 66 ; however, none of these genomic variants appear to explain a significant part of the high interindividual variability in UGT2B7 gene expression.…”

Section: Emerging Mechanisms As a Source Of Variability In The Glucurmentioning

confidence: 99%

Pharmacogenomics of Human Uridine Diphospho-Glucuronosyltransferases and Clinical Implications

Guillemette

Lévesque

Rouleau

2014

Clin Pharmacol Ther

136

145

View full text Add to dashboard Cite

Glucuronidation by uridine diphospho‐glucuronosyltransferase enzymes (UGTs) is a major phase II biotransformation pathway and, complementary to phase I metabolism and membrane transport, one of the most important cellular defense mechanisms responsible for the inactivation of therapeutic drugs, other xenobiotics, and endogenous molecules. Interindividual variability in UGT pathways is significant and may have profound pharmacological and toxicological implications. Several genetic and genomic processes underlie this variability and are discussed in relation to drug metabolism and diseases such as cancer. Clinical Pharmacology & Therapeutics (2014); 96 3, 324–339. advance online publication 16 July 2014. doi:

show abstract

“…Proteins (30 mg) were separated on SDS-polyacrylamide gels (10%) and transferred to nitrocellulose membranes for Western blotting. The anti-UGT2B7 antibody was developed in our laboratory as previously reported (Kerdpin et al, 2009;Hu et al, 2014). The anti-p53 antibody (FL-393) was purchased from Santa Cruz Biotechology (Dallas, TX).…”

Section: Methodsmentioning

confidence: 99%

Epirubicin Upregulates UDP Glucuronosyltransferase 2B7 Expression in Liver Cancer Cells via the p53 Pathway

Hu¹,

Rogers²,

Mackenzie³

2014

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

Anthracyclines are effective genotoxic anticancer drugs for treating human malignancies; however, their clinical use is limited by tumor resistance and severe cardiotoxicity (e.g., congestive heart failure). Epirubicin (EPI) is less cardiotoxic compared with other canonical anthracyclines (e.g., doxorubicin). This has been attributed to its unique glucuronidation detoxification pathway. EPI is primarily inactivated by UDPglucuronosyltransferase 2B7 (UGT2B7) in the liver. Hence, the regulation of hepatic UGT2B7 expression is critical for EPI systemic clearance but remains poorly characterized. We show herein that EPI upregulates UGT2B7 expression in hepatocellular carcinoma (HCC) HepG2 and Huh7 cells. Our analyses of deleted and mutated UGT2B7 promoter constructs identified a p53 response element (p53RE) in the UGT2B7 promoter. EPI stimulated UGT2B7 promoter activity via this p53RE and enhanced in vivo p53 binding at this p53RE in HepG2 cells. Knockdown of p53 expression by small interfering RNA silencing technology significantly repressed the capacity of EPI to stimulate UGT2B7 transcription. Furthermore, the p53 activator nutlin-3a significantly enhanced UGT2B7 expression and recruited the p53 protein to the UGT2B7 p53RE in HepG2 cells. Collectively, our results demonstrated that EPI promotes its own detoxification via the p53-mediated pathway. This regulation may contribute to tumor resistance to EPI-containing HCC chemotherapy and may also provide a new explanation for the reduced cardiotoxicity of EPI compared with other anthracyclines. Our finding also suggests that upon exposure to genotoxic agents, detoxifying genes are activated by the p53-mediated pathway to clear genotoxic agents locally within the tumor site or even systemically through the liver.

show abstract

Polymorphisms and Haplotypes of the UDP-Glucuronosyltransferase 2B7 Gene Promoter

Cited by 21 publications

References 51 publications

Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: review of current knowledge and comparison with selected European populations

Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: review of current knowledge and comparison with selected European populations

Pharmacogenomics of Human Uridine Diphospho-Glucuronosyltransferases and Clinical Implications

Epirubicin Upregulates UDP Glucuronosyltransferase 2B7 Expression in Liver Cancer Cells via the p53 Pathway

Contact Info

Product

Resources

About