Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid. Drug Metab Dispos

Laval University, Quebec City, Quebec, Canada
Drug Metabolism and Disposition (Impact Factor: 3.25). 10/2006; 34(9):1539-45. DOI: 10.1124/dmd.106.010553
Source: PubMed


Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), a standard immunosuppressive drug approved for clinical use in the prevention of acute allograft rejection after organ transplantation. This study examines the role of the genetic variants of UDP-glucuronosyltransferase (UGT) 1A8 and 2B7 enzymes involved in the formation of the primary metabolite of MPA, the inactive phenolic glucuronide (MPAG), and the reactive acyl glucuronide (AcMPAG). The first exon of UGT1A8 was first resequenced in the region encoding for the substrate binding domain in 254 Caucasians and 41 African Americans. Eight nonsynonymous changes were observed and led to the following amino acid substitutions: S43L, H53N, S126G, A144V, A173G, A231T, T240A, and C277Y. Thirteen haplotypes were inferred, comprising only two previously described alleles, namely, UGT1A8*2 (A173G) and UGT1A8*3 (C277Y). Upon stable expression in human embryonic kidney 293 cells, the UGT1A8*3 (C277Y), *5 (G173A240), *7 (A231T), *8 (S43L), and *9 (N53G) proteins were associated with the most profound decreases in the formation of MPAG and AcMPAG, indicating that these amino acids are critical for substrate binding and enzyme function. Altogether, the low-activity UGT1A8 enzymes are carried by 2.8 to 4.8% of the population. The variant of the UGT2B7 protein (UGT2B7*2 Y268), the main enzyme involved in the formation of AcMPAG, demonstrated a catalytic efficiency comparable with that of UGT2B7*1 (H268). In conclusion, although the common UGT2B7*2 variant is predicted to have limited impact, several UGT1A8 variants identified may potentially account for the large interindividual variance in MMF pharmacokinetics and deserve further clinical investigations.

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    • "It has been demonstrated that in renal transplant recipients, carriers of either or both polymorphisms had lower MPA AUC and C 0 (Johnson et al, 2008; Kuypers et al., 2005; van Schaik et al., 2009). On the other hand, UGT1A8*3 (P277C>Y) polymorphism results in an approximately 30-fold reduction in MPAG formation (Bernard et al., 2006). MPA inhibits inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the pathway for purine synthesis.. "

    Kidney Transplantation - New Perspectives, 08/2011; , ISBN: 978-953-307-684-3
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    • "The UGT2B7 gene is polymorphic with a frequent non-synonymous variant 802 C > T leading to a histidine to tyrosine substitution in codon 268 (His268Tyr). The functional impact of this polymorphism is unclear as studies have shown lower [8-12], similar [13-15], and even higher enzyme activity of the UGT2B7268Tyr isoform [16-18]. Two in vitro studies showed no impact of the UGT2B7His268Tyr genotype on the epirubicin glucuronide formation [6,19]. "
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    ABSTRACT: Epirubicin is a common adjuvant treatment for breast cancer. It is mainly eliminated after glucuronidation through uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7). The present study aimed to describe the impact of the UGT2B7(His268Tyr) polymorphism on invasive disease-free survival in breast cancer patients after epirubicin treatment. This is a pharmacogenetic study based on samples collected from 745 breast cancer patients of the Austrian Tumor of breast tissue: Incidence, Genetics, and Environmental Risk factors (TIGER) cohort who did not present metastases at baseline. This cohort included 205 women with epirubicin-based combination chemotherapy, 113 patients having received chemotherapy without epirubicin and 427 patients having received no chemotherapy at all. Of the epirubicin-treated subgroup, 120 were subsequently treated with tamoxifen. For all women UGT2B7(His268Tyr) was genotyped. Invasive disease-free survival was assessed using Kaplan-Meier and Cox's proportional hazard regression analysis. Among the 205 epirubicin-treated patients, carriers of two UGT2B7(268Tyr) alleles had a mean invasive disease-free survival of 8.6 (95% confidence interval (CI) 7.9 to 9.3) years as compared to 7.5 (95% CI 6.9 to 8.0) years in carriers of at least one UGT2B7(268His) allele (adjusted hazard ratio (HR) = 2.64 (95% CI 1.22 to 5.71); P = 0.014). In addition, the impact of the UGT2B7(His268Tyr) polymorphism became even more pronounced in patients subsequently treated with tamoxifen (adjusted HR = 5.22 (95% CI 1.67 to 26.04); P = 0.015) whereas no such difference in invasive disease-free survival was observed in patients not receiving epirubicin. Breast cancer patients carrying the UGT2B7(268Tyr/Tyr) genotype may benefit most from adjuvant epirubicin-based chemotherapy. These results warrant confirmation in further studies.
    Breast cancer research: BCR 06/2011; 13(3):R57. DOI:10.1186/bcr2894 · 5.49 Impact Factor
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    • "UGT1A6_i2 microsomes and UGT1A6_i1/ UGT1A6_i2 microsomes were also evaluated. The experiments were conducted at 37°C with ϳ30 ␮g of UGT membrane protein, 50 mM Tris-HCl (pH 7.5), 10 mM MgCl, 2 mM UDP-glucuronic acid, pepstatin, and phosphatidylcholine , as described previously (Bernard et al., 2006). The reactions were terminated by adding 100 ␮l of methanol ϩ 0.1% tetrafluoroacetic acid, and the mixtures were centrifuged at 14,000g for 10 min before analysis. "
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    ABSTRACT: Tissue iron overload constitutes a major health problem for people who require regular blood transfusions, such as those with beta-thalassemia major. Deferiprone is a hydroxypyridinone iron chelator used therapeutically to remove this excess iron and prevent tissue damage. Deferiprone is metabolized by UDP-glucuronosyltransferases (UGTs) into deferiprone 3-O-glucuronide (DG), but a systematic evaluation of the contribution of individual human UGTs and the impact of genetic variations of UGTs have not been conducted. Sixteen human UGT1A and UGT2B were studied for deferiprone glucuronidation, and their clearances were compared in human tissue samples. DG was measured by liquid chromatography coupled with mass spectrometry. DG was primarily produced in vitro by UGT1A6, and a second glucuronide metabolite was discovered. UGT1A6, as well as liver and kidney human microsomes, had similar kinetic profiles and clearance (Cl(int) = 1.4-3.0 mul/min/mg), but clearance by intestinal microsomes was much lower (0.04 mul/min/mg). Binding of deferiprone to microsomal preparations was not significant. Genetic variants of UGT1A6 had K(m) values similar to the reference protein (UGT1A6*1), but their V(max) values were reduced by 25 to 70%. The UGT1A6 splice variant isoform 2, detected in the liver and kidney, had no transferase activity for deferiprone. When UGT1A6_i2 was coexpressed with the classic UGT1A6_i1 isoform, velocity was reduced for deferiprone but remained similar for 4-nitrophenol or serotonin glucuronidation. In conclusion, deferiprone glucuronidation seems to depend almost totally on UGT1A6, especially in the liver. Genetic variations and differences in the expression of splice variants represent a potential source of variation in deferiprone metabolism.
    Drug metabolism and disposition: the biological fate of chemicals 11/2008; 37(2):322-9. DOI:10.1124/dmd.108.023101 · 3.25 Impact Factor
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