Certain genetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who are homozygous or heterozygous for these types of genetic variations may have increased levels of TGN metabolites and an increased risk of severe bone marrow suppression (myelosuppression) when receiving azathioprine. In many ethnicities, TPMT polymorphisms that result in decreased or absent TPMT activity occur with a frequency of approximately 5%, meaning that about 0.25% of patients are homozygous for these variants. However, an assay of TPMT activity in red blood cells or a TPMT genetic test can identify patients with reduced TPMT activity, allowing for the adjustment of azathioprine dose or avoidance of the drug entirely. The FDA-approved drug label for azathioprine recommends testing for TPMT activity to identify patients at risk for myelotoxicity. Indeed, testing for TPMT activity is one of the few examples of pharmacogenetics being translated into routine clinical care. Missense SNP in NUDT15 (e.g., rs116855232, inducing R139C)) has been identified to be a causal factor for AZA-induced leukopenia through a genome wide association study (GWAS) in East Asians. Cancers
Azathioprine is listed as a human carcinogen in the 12th Report on Carcinogens by the National Toxicology Program of U.S. Department of Health and Human Services, asserting that it is "known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans."
Because actively replicating cells (such as cancer cells and the T cells and B cells of the immune system) are most active in synthesizing purine, making new DNA, these cells are most strongly affected. A portion of the nucleotides is additionally phosphorylated to the triphosphate forms. These  bind to GTP-binding protein Rac1, blocking synthesis of the protein Bcl-xL, thus sending activated T cells and mononuclear cells into apoptosis (programmed cell death). Increased apoptosis of mononuclear cells is seen in inflammatory bowel disease patients treated with azathioprine. Chemistry
Azathioprine is a thiopurine linked to a second heterocycle (an imidazole derivative) via a thioether. It is a pale yellow solid with a slightly bitter taste and a melting point of 238–245 °C. It is practically insoluble in water and only slightly soluble in lipophilic solvents such as chloroform, ethanol, and diethylether. It dissolves in alkaline aqueous solutions, where it hydrolyzes to 6-mercaptopurine.Azathioprine is synthesized from 5-chloro-1-methyl-4-nitro-1H-imidazole and 6-mercaptopurine in dimethyl sulfoxide. The synthesis of the former starts with an amide from methylamine and diethyl oxalate, which is then cyclized and chlorinated with phosphorus pentachloride; the nitro group is introduced with nitric and sulfuric acid. History
Azathioprine was synthesized by George Herbert Hitchings and Gertrude Elion in 1957 (named BW 57-322) to produce 6-MP in a metabolically active, but masked form, and at first used as a chemotherapy drug.Robert Schwartz investigated the effect of 6-MP on the immune response in 1958 and discovered that it profoundly suppresses the formation of antibodies when given to rabbits together with antigens.