methylation prevents mercaptopurine from further conversion into active, cytotoxic thioguanine nucleotide (TGN) metabolites. 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 mercaptopurine. 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 people are homozygous for these variants. However, an assay of TPMT activity in red blood cells or a TPMT genetic test can identify people with reduced TPMT activity, allowing for the adjustment of mercaptopurine dose or avoidance of the drug entirely. The FDA-approved drug label for mercaptopurine recommends testing for TPMT activity to identify people at risk for myelotoxicity. Testing for TPMT activity is an example of pharmacogenetics being translated into routine clinical care. History 6-MP was discovered by Nobel Prize winning scientists Gertrude B. Elion and George H. Hitchings at Burroughs Wellcome in Tuckahoe, New York, and was clinically developed in collaboration with investigators at Memorial Hospital (now Memorial Sloan Kettering Cancer Center in New York City). The collaboration was initiated by Cornelius P. Rhoads who had run chemical weapons programs for the US army and had been involved in the work that led to the discovery that nitrogen mustards could potentially be used as cancer drugs, and had become the director of Memorial in 1948. See also Azathioprine Tioguanine References Further reading External links Purines Thiocarbonyl compounds IARC Group 3 carcinogens Purine antagonists World Health Organization essential medicines Wikipedia medicine articles ready to translate