TY - JOUR T1 - Divergent Activities of Human Glutathione Transferases in the Bioactivation of Azathioprine JF - Molecular Pharmacology JO - Mol Pharmacol SP - 747 LP - 754 DO - 10.1124/mol.106.025288 VL - 70 IS - 2 AU - Birgitta I. Eklund AU - My Moberg AU - Jonas Bergquist AU - Bengt Mannervik Y1 - 2006/08/01 UR - http://molpharm.aspetjournals.org/content/70/2/747.abstract N2 - Azathioprine is a thiopurine prodrug clinically used for immunosuppression in the treatment of inflammatory diseases and in pharmacological regimens of organ transplantations. Its pharmacological action is based on the release of 6-mercaptopurine, but the biochemical processes underlying this biotransformation have remained obscure. In this investigation, human glutathione transferases (GSTs) from seven distinct classes were assayed with azathioprine. GSTs A1-1, A2-2, and M1-1, all abundantly expressed in human liver, displayed the highest activity among the 14 GSTs tested. The uncatalyzed reaction of azathioprine with glutathione was estimated to be less than 1% of the GST-catalyzed biotransformation. GST M1-1 is polymorphic with a frequently occurring null allele, and GSTs A1-1 and A2-2 show variable expression levels in human subjects, implying significant differences in the rate of 6-mercaptopurine release from azathioprine. Individuals expressing high GST activity are apparently predisposed for adverse reactions to azathioprine treatment, both by promoting excessively high concentrations of free 6-mercaptopurine and its toxic metabolites and by depleting cellular glutathione. These novel aspects of GST-dependent azathioprine biotransformation have not been considered previously. ER -