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Divergent Activities of Human Glutathione Transferases in the Bioactivation of Azathioprine

Department of Biochemistry and Organic Chemistry (B.I.E., B.M.), and Department of Physical and Analytical Chemistry (M.M., J.B.), Uppsala University, Uppsala, Sweden

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.

Address correspondence to: Dr. Bengt Mannervik, Uppsala University, Biomedical Center, Box 576, SE-751 23 Uppsala, Sweden. E-mail: Bengt.Mannervik{at}biokemi.uu.se