UGT1A9 is the primary enzyme and is expressed predominantly in liver and kidneys and, to a lesser extent, in the gastrointestinal tract. UGT1A8 and 1A10 are expressed throughout the gastrointestinal tract [69]. In vitro studies have shown that polymorphisms in the UGT1A9 gene result in significant alteration

of the UGT enzymatic activity. Two polymorphisms, both in the promoter region of the UGT1A9 gene (C-275T>A) and (C-2152C>T), result in higher MPA glucuronidation rates [70], whereas the UGT1A9*3 (P 33M>T) polymorphism results in decreased enzyme activity and lower glucuronidation Epigenetics inhibitor rate of MPA compared to the wild-type [71]. Clinical investigation of the effects of the UGT1A9-275T>A and -2152C>T polymorphisms in kidney transplant recipients

has demonstrated that carriers of either or both polymorphisms had lower MPA area under the curve (AUC) and trough concentrations [59,60,62]. Polymorphisms have been also identified in the UGT1A8 gene. It has been reported that UGT1A8*3 (P 277C>Y) polymorphism results in an approximately 30-fold reduction in MPAG formation. This reduction has been attributed to the mutation effects on substrate affinity and the rate of MPAG formation [72]. Additionally, in a prospective study Sombogaard et al.[56] have recently measured the target enzyme click here IMPDH activity, MPA plasma concentrations and eight polymorphisms of inosine IMPDH type II in de novo kidney transplant recipients 6 days post-transplantation while on mycophenolate mofetil (MMF) treatment. Ten of 101 patients (10%) were heterozygous and two of 101 patients (2%) homozygous for IMPDH type II 3757T>C. The allele frequency was 6·9%. The IMPDH activity over 12 h AUC was 49% higher for patients with an IMPDH type II 3757C variant. The IMPDH activity measured before transplantation was not significantly different between IMPDH type II 3757TT wild-type and variant carrier patients.

However, additional in vivo studies need to be performed to assess the potential clinical utility of these findings. Recent data indicate that genetic mutations may influence the sensitivity of mTOR inhibitors (Table 1). This represents a relatively new family of anti-cancer and immunosuppressive agents, currently including sirolimus and its derivates, CCI-779 and RAD001 (everolimus). These drugs form complexes with an intracellular immunophillin oxyclozanide (FKBP) which bind to the kinase mTOR. This kinase controls the phosphorylation of proteins that regulate the translation of mRNAs encoding regulators of the cell cycle, such as p70S6 kinase. Thus, inhibition of this pathway arrests the cellular cycle to G1 phase [2]. Huang and Houghton [73] have recently reviewed the current knowledge of intrinsic mTOR resistance mechanism. This phenomenon could involve mutations of FKBP12 or mTOR as well as mutations or defects of mTOR-regulated proteins, including S6K1-, 4E-BP1- and PP2A-related phosphatases and p27 that can render mTOR inhibitors insensitive [74].