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).
Modén, O, Mannervik, B
Bergquist, J, Eklund, BI, Moberg, M, Mannervik, B
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
Modén, O, Mannervik, B, Tars, K, Zhang, W
Caprioli, RM, Lin, SN, van Buren, CT, Floyd, M, Jessup, K, Wang, TP, Kahan, BD
glutathione transferase activity of GSTA1,A2,M1 dimers [cytosol]
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