These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Influence of the UGT2B7 promoter region and exon 2 polymorphisms and comedications on Acyl-MPAG production in vitro and in adult renal transplant patients.
    Author: Djebli N, Picard N, Rérolle JP, Le Meur Y, Marquet P.
    Journal: Pharmacogenet Genomics; 2007 May; 17(5):321-30. PubMed ID: 17429314.
    Abstract:
    INTRODUCTION: The polymorphic enzyme UGT2B7 metabolizes mycophenolic acid into acyl-mycophenolic acid-glucuronide (AcMPAG), a presumably toxic metabolite. This study aimed at investigating in vitro and in vivo the impact on AcMPAG production of: (i) the UGT2B7 gene G-842A single nucleotide polymorphism, in complete linkage disequilibrium with most other known single nucleotide polymorphisms in the promoter region of this gene and with the C802T single nucleotide polymorphism in exon 2 (UGT2B*2); and (ii) of the other immunosuppressants given to renal transplant patients in association with mycophenolate mofetil. METHODS: We compared the production of AcMPAG by human liver microsomes genotyped for the UGT2B7 G-842A and C802T single nucleotide polymorphisms, and plasma AcMPAG concentrations in genotyped renal transplant patients administered mycophenolate mofetil associated with sirolimus (n=40), tacrolimus (n=24) or cyclosporin (n=28) and decreasing doses of corticosteroids, over the first 3 months after transplant. The effect of corticosteroids was also investigated in vitro using rats' liver microsomes. RESULTS: The two polymorphisms studied were in complete reverse linkage disequilibrium. AcMPAG production was 1.25 and 1.56-fold higher in G-842A and -842AA human liver microsomes, respectively, compared with GG-842 human liver microsomes (P=0.01). Enzyme kinetics showed 1.4 and 3.7-fold higher Vmax in the respective pools of human liver microsomes. Km values were 0.20, 0.25 and 0.44 mmol/l for the GG-842, G-842A and -842AA genotypes, respectively. This clear increase in Vmax is in favor of the implication of the promoter region polymorphisms, whereas the slighter increase in Km might be due to the UGT2B7*2 single nucleotide polymorphism. Consistently, the UGT2B7 genotype significantly influenced AcMPAG area under the curve (AUC0-9 h)/dose in patients on sirolimus at months 1 and 3 after transplant (P=0.04 for both). No effect was observed in patients on tacrolimus and possibly also on cyclosporin, maybe owing to pharmacokinetic interaction with mycophenolate. AcMPAG production was increased in corticosteroid-induced rat liver microsomes, consistent with the observed in-vivo decrease of mycophenolic acid metabolites AUC0-9 h/dose with time after transplant. CONCLUSION: Both UGT2B7 polymorphisms and co-medications significantly influenced AcMPAG production, but cyclosporin and tacrolimus hindered the phenotypic impact of this trait.
    [Abstract] [Full Text] [Related] [New Search]