Reactome | GST dimers cleave AZA to 6MP

GST dimers cleave AZA to 6MP

Stable Identifier

R-HSA-9748996

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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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