Received for publication April 7, 2006.
Revised May 16, 2006.
Accepted for publication May 22, 2006.

Divergent Activities of Human Glutathione Transferases in the Bioactivation of Azathioprine

Abstract

Azathioprine (Aza) 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 (6-MP), but the biochemical processes underlying this biotransformation have remained obscure. Human glutathione transferases (GSTs) from seven distinct classes were assayed with Aza, and 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 Aza 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-MP release from Aza. Individuals expressing high GST activity are apparently predisposed for adverse reactions to Aza treatment, both by promoting excessively high concentrations of free 6-MP and its toxic metabolites, and by depleting cellular glutathione. These novel aspects of GST-dependent Aza biotransformation have not previously been considered.

Key words: Glutathione S-transferases, Glutathione, Nucleoside/Nucleotide derivatives, Pharmacokinetics, metabolism and activation