PT  - JOURNAL ARTICLE
AU  - Birgitta I. Eklund
AU  - My Moberg
AU  - Jonas Bergquist
AU  - Bengt Mannervik
TI  - Divergent Activities of Human Glutathione Transferases in the Bioactivation of Azathioprine
AID  - 10.1124/mol.106.025288
DP  - 2006 Aug 01
TA  - Molecular Pharmacology
PG  - 747--754
VI  - 70
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/70/2/747.short
4100  - http://molpharm.aspetjournals.org/content/70/2/747.full
SO  - Mol Pharmacol2006 Aug 01; 70
AB  - 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.