title: Divergent activities of human glutathione transferases in the bioactivation of azathioprine.
abstract: 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.
authors.affiliation: Department of Biochemistry and Organic Chemistry, Uppsala University, Biomedical Center, Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Birgitta I
authors.initials: BI
authors.lastname: Eklund
authors.forename: My
authors.initials: M
authors.lastname: Moberg
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergquist
authors.forename: Bengt
authors.initials: B
authors.lastname: Mannervik
mesh_terms: D001379:Azathioprine / Q000009:adverse effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism*; D007700:Kinetics; D013058:Mass Spectrometry; D008780:Methyltransferases / Q000502:physiology
chemical_list: D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D005982:Glutathione Transferase; D001379:Azathioprine