GST dimers cleave AZA to 6MP

Stable Identifier
Reaction [transition]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
Azathioprine (AZA) was developed as a prodrug to 6-mercaptopurine (6MP) in order to counter the high first-pass metabolism of 6MP in the intestine. A nitroimidazol group was added to 6MP to create AZA. Human glutathione transferases (GSTs) A1-1, A2-2, and M1-1, all highly expressed in human liver, display high enzymatic activity towards AZA, cleaving it to release the antimetabolite 6-mercaptopurine (6MP) (Eklund et al. 2006, Moden & Mannervik 2014). After oral administration AZA is undetectable in blood, while 6MP appears after either oral or iv AZA administration (Lin et al. 1980). This is because, after ingestion, around 88% of AZA is converted to 6MP. The uncatalyzed reaction of AZA with glutathione is estimated to be <1% of the GST-catalyzed reaction. 6MP is released via a tetrahedral intermediate formed by nucleophilic attack of the glutathione thiolate (GS−). The reaction is thought to be promoted by H-bonding or other polar interactions (Zhang et al. 2012). GSTs variants may be associated with AZA efficacy and pharmacokinetics (Lufaco et al. 2019).

Literature References
PubMed ID Title Journal Year
24974183 Glutathione transferases in the bioactivation of azathioprine

Modén, O, Mannervik, B

Adv Cancer Res 2014
16717136 Divergent activities of human glutathione transferases in the bioactivation of azathioprine

Bergquist, J, Eklund, BI, Moberg, M, Mannervik, B

Mol Pharmacol 2006
30987408 Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants

Ventura, A, Martelossi, S, Franca, R, Lora, A, Stocco, G, Lucafò, M, Decorti, G, Favretto, D, Cecchin, E, Bramuzzo, M, Naviglio, S, Malusà, N, Toffoli, G

Genes (Basel) 2019
22444596 Structure-based redesign of GST A2-2 for enhanced catalytic efficiency with azathioprine

Modén, O, Mannervik, B, Tars, K, Zhang, W

Chem Biol 2012
6989049 Quantitation of plasma azathioprine and 6-mercaptopurine levels in renal transplant patients

Caprioli, RM, Lin, SN, van Buren, CT, Floyd, M, Jessup, K, Wang, TP, Kahan, BD

Transplantation 1980
Event Information
Catalyst Activity

glutathione transferase activity of GSTA1,A2,M1 dimers [cytosol]

Orthologous Events
Cite Us!