Azathioprine: old drug, new actions

A knowledge of the biochemical loci of action of 6-MP in the inhibition of nucleic acid synthesis is not sufficient to explain the effects of the thiopurines on the immune system. —Gertrude B. Elion (Winner of 1988 Nobel Prize in Medicine for “important principals of drug development”; codiscovered 6-MP and azathioprine with George Hitchings) (1) Azathioprine is among the oldest pharmacologic immunosuppressive agents in use today. Initially developed as a long-lived prodrug of 6-mercaptopurine (6-MP), it was quickly found to have a more favorable therapeutic index. It was soon found that 6-MP could produce remissions in childhood acute leukemia (1), and later, that azathioprine could prolong renal allograft survival (2). Over the past 50 years, azathioprine has been used in the treatment of hematologic malignancies, rheumatologic diseases, solid organ transplantation, and inflammatory bowel disease. The drug is a purine analog, and the accepted mechanism of action is at the level of DNA (1, 3). Both in vitro and in vivo, azathioprine is metabolized to 6-MP through reduction by glutathione and other sulphydryl-containing compounds and then enzymatically converted into 6-thiouric acid, 6-methyl-MP, and 6-thioguanine (6-TG) (1, 3). Ultimately, azathioprine can then become incorporated into replicating DNA and can also block the de novo pathway of purine synthesis. It is this action that is thought to contribute to its relative specificity to lymphocytes due to their lack of a salvage pathway. However, the effects on the blockade of DNA replication have never fully explained all of the laboratory and clinical findings of azathioprine-induced immunosuppression.