Study on the association of UGT1A9 gene c.98T>C polymorphism and mycophenolic acid plasma levels in renal transplant patients

Abstract

ABSTRACT. Mycophenolate mofetil (MMF) is a prodrug active only after its hydrolysis to mycophenolic acid (MPA). The UGT1A9 enzyme is of special interest since it is the main enzyme involved in the glucuronidation of MPA. Single nucleotide polymorphisms (SNPs) in the UGT1A9 gene may be responsible for individual differences in the pharmacokinetics of MMF. Expression levels and the activity of UGT1A9 may depend on the presence of some SNPs located in the gene promoter region (-2152C>T and -275T>A), as well as changes in the coding region (c.98T>C). The objective of this study was to evaluate the effect of allelic variants of the UGT1A9 c.98T>C polymorphism (rs72551330; g. 87289T>C) on MMF metabolism in 2 L.R. Ruschel et al.Genetics and Molecular Research 16 (2): gmr16029598 renal transplant patients. MPA and MPA 7-O glucuronide (MPAG) levels were determined on plasma samples of kidney transplant patients (N = 39) by high-performance liquid chromatography using ultraviolet detection. DNA was isolated from leukocytes and stored at -20°C. The presence of SNPs was investigated using polymerase chain reaction, followed by amplicon sequencing. The analysis of the UGT1A9 c.98T>C polymorphism revealed that all study patients presented the TT genotype. Diverse MPA and MPAG plasma concentrations were detected, including therapeutic, subtherapeutic, and toxic levels. A standardized molecular method permitted identification of UGT1A9 c.98T>C polymorphism genotypes in the examined renal transplant patients. All individuals of the study group presented the same genotype (c.98TT) for that polymorphism. Thereby, no association between the c.98T>C polymorphism and MPA and MPAG plasma levels could be evaluated, despite different levels of these compounds being observed.

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“…Ugt1a9 encodes an enzyme responsible for hydroxyl and phenol glucuronidation. Substrates of UGT1A9 involve lots of nature products such as flavonoids, tanshinone, and some alkaloids [16][17][18][19], as well as important synthetic drugs such as propofol [20], 4methylumbelliferone [21], mycophenolic acid [22], and morphine [23]. In addition, UGT1A9 also participated in metabolism processes of endogenous signaling molecules like estradiol [24].…”