Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene

Innocenti, Federico; W, Liu; Fackenthal, Donna Lee; Ramı́rez, Jacqueline; Chen, Peixian; Ye, Xin; Wu, Xiaolin; Zhang, Wei; Mirkov, Snezana; Das, Soma; Cook, Edwin H.; Ratain, Mark J.

doi:10.1097/fpc.0b013e3283037fe4

Cited by 77 publications

(82 citation statements)

References 23 publications

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“…Regarding the most common UGT2B7 nonsynonymous single nucleotide polymorphism (UGT2B7*2), it was reported that UGT2B7*2 was not associated with altered morphine 3 and 6‐glucuronidation in adult liver microsomes ( n = 53) 33. A comprehensive PG study found that diplotypes containing haplotype #4 in UGT2B7 resulted in a significant increase in the formation of morphine 3 and 6‐glucuronidation (45% and 56%, respectively) compared with diplotypes without the haplotype #4 34. Based on the observed activity changes as a result of UGT2B7 genetic variants, the maximum velocity of UGT2B7‐mediated morphine glucuronidation in human liver microsomes was scaled from 50–150% of the default value (set at 100%), as shown in Table 1, 4, 5, 6, 14, 15, 16, 17, 18 for the simulations in virtual pediatric and adult healthy subjects.…”

Section: Methodsmentioning

confidence: 99%

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

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Fukuda

Johnson

et al. 2016

CPT Pharmacom & Syst Pharma

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Morphine shows large interindividual variability in its pharmacokinetics; however, the cause of this has not been fully addressed. The variability in morphine disposition is considered to be due to a combination of pharmacogenetic and physiological determinants related to morphine disposition. We previously reported the effect of organic cation transporter (OCT1) genotype on morphine disposition in pediatric patients. To further explore the underlying mechanisms for variability arising from relevant determinants, including OCT1, a physiologically based pharmacokinetic (PBPK) model of morphine was developed. The PBPK model predicted morphine concentration‐time profiles well, in both adults and children. Almost all of the observed morphine clearances in pediatric patients fell within a twofold range of median predicted values for each OCT1 genotype in each age group. This PBPK modeling approach quantitatively demonstrates that OCT1 genotype, age‐related growth, and changes in blood flow as important contributors to morphine pharmacokinetic (PK) variability.

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Section: Methodsmentioning

confidence: 99%

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

Emoto

Fukuda

Johnson

et al. 2016

CPT Pharmacom & Syst Pharma

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“…A study that used human livers from white individuals (n ϭ 54) identified a particular haplotype associated with UGT2B7 activity (27 ). This haplotype, with an MAF of 12%, included the intronic variant IVS1 ϩ 985AϾG (rs62298861), which was consistently correlated with increased mRNA expression and increased glucuronidation.…”

Section: Ugt2b7mentioning

confidence: 99%

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

et al. 2017

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BACKGROUND The use of opioids to alleviate pain is complicated by the risk of severe adverse events and the large variability in dose requirements. Pharmacogenetics (PGx) could possibly be used to tailor pain medication based on an individual's genetic background. Many potential genetic markers have been described, and the importance of genetic predisposition in opioid efficacy and toxicity has been demonstrated in knockout mouse models and human twin studies. Such predictors are especially of value for neonates and young children, in whom the assessment of efficacy or side effects is complicated by the inability of the patient to communicate this properly. The current problem is determining which of the many potential candidates to focus on for clinical implementation. CONTENT We systematically searched publications on PGx for opioids in 5 databases, aiming to identify PGx markers with sufficient robust data and high enough occurrence for potential clinical application. The initial search yielded 4257 unique citations, eventually resulting in 852 relevant articles covering 24 genes. From these genes, we evaluated the evidence and selected the most promising 10 markers: cytochrome P450 family 2 subfamily D member 6 (CYP2D6), cytochrome P450 family 3 subfamily A member 4 (CYP3A4), cytochrome P450 family 3 subfamily A member 5 (CYP3A5), UDP glucuronosyltransferase family 2 member B7 (UGT2B7), ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C member 3 (ABCC3), solute carrier family 22 member 1 (SLC22A1), opioid receptor kappa 1 (OPRM1), catechol-O-methyltransferase (COMT), and potassium voltage-gated channel subfamily J member 6 (KCNJ6). Treatment guidelines based on genotype are already available only for CYP2D6. SUMMARY The application of PGx in the management of pain with opioids has the potential to improve therapy. We provide a shortlist of 10 genes that are the most promising markers for clinical use in this context.

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“…This post-transcriptional mechanism has been reported for genes involved in drug metabolism, most notably cytochrome P450 (P450) (Turman et al, 2006), sulfotransferases (He et al, 2005), glutathione S-transferase (Ross and Board, 1993), and UDP-glucuronosyltransferases (UGTs) . UGT1A family members are derived from the use of alternative promoters and exons 1, whereas UGT2B7 is subjected to extensive alternative splicing (Innocenti et al, 2008;Guillemette et al, 2010;Ménard et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Modulation of the UGT2B7 Enzyme Activity by C-Terminally Truncated Proteins Derived from Alternative Splicing

et al. 2013

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The enzyme UGT2B7 is one of the most active UDP-glucuronosyltransferases (UGTs) involved in drug metabolism and in maintaining homeostasis of endogenous compounds. We recently reported the existence of 22 UGT2B7 mRNAs, two with a classic 59 region but alternative 39 ends namely UGT2B7_v5 (containing a novel terminal exon 6b) and _v7 (exon 5 excluded) that encode enzymatically inactive isoforms 2 and 4 (i2 and i4), respectively. The v1 mRNA encoding the UGT2B7 enzyme (renamed isoform 1 or i1) is coexpressed with the splice variants v5 and v7 in human liver, kidney, and small intestine and the hepatic cell lines HepG2 and C3A. The presence of alternate v5 and v7 transcripts in isolated polysomes from these hepatic cells further supports endogenous protein translation. Cellular fractionation of clonal HEK293 cell lines overexpressing UGT2B7 isoforms demonstrates that i1, i2, and i4 proteins colocalize in the microsomal/Golgi fraction, whereas i2 and i4 can also be found in the cytosol; a finding sustained by immunofluorescence experiments using tagged proteins. By modifying splice variant abundance in overexpression in HEK293 and HepG2 cells as well as RNA interference experiments in HepG2 and C3A cells, we observe drug glucuronidation phenotypes compatible with variant-mediated repression of UGT2B7 activity without consequent alteration of the apparent enzyme affinity (K m ). Finally, coimmunoprecipitation experiments support a direct proteinprotein interaction of i2 and i4 proteins with the functional UGT2B7 enzyme as a potential causative mechanism. These findings point toward a novel autoregulatory mechanism of the UGT2B7 glucuronidation pathway by naturally occurring alternative i2 and i4 proteins.

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Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene

Cited by 77 publications

References 23 publications

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

Modulation of the UGT2B7 Enzyme Activity by C-Terminally Truncated Proteins Derived from Alternative Splicing

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