, Volume 20, Issue 7-8, pp 637-658

Thiopurine methyltransferase biochemical genetics: Human lymphocyte activity

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Abstract

The level of human erythrocyte (RBC) thiopurine methyltransferase (TPMT) activity is inherited as a monogenic trait. Experiments were performed to determine whether the level of TPMT activity in the human lymphocyte is regulated in parallel with RBC TPMT. Supernatants of lymphocyte homogenates contained TPMT activity. Lymphocyte TPMT activity was maximal at a reaction pH of 6.6. The apparent K m value for 6-mercaptopurine, the thiopurine substrate for the reaction, was 8.1×10−4 m, and the apparent K m value for S-adenosyl-l-methionine, the methyl donor for the reaction, was 3.6×10−6 m. The average TPMT activity in lymphocytes isolated from blood of 55 randomly selected subjects was 11.0±0.4 units/109 cells (mean ± SE), with a range of from 4.8 to 17.7 units/109 cells. There was a significant correlation of relative RBC with relative lymphocyte TPMT activity in blood samples from these 55 subjects, with a correlation coefficient of 0.563 (P<0.001). The correlation coefficient for RBC with platelet enyzme activities in these same subjects was also highly significant (r=0.680, P<0.001). Blood samples from four previously identified subjects who were homozygous for the allele TPMT L, subjects who lacked detectable RBC enzyme activity, also lacked detectable lymphocyte and platelet TPMT activities. These results were compatible with the conclusion that the genetic polymorphism which regulates RBC TPMT activity also regulates the level of human lymphocyte and platelet TPMT activities.

Supported in part by NIH Grants GM 28157 and NS 11014. Dr. Weinshilboum is a Burroughs Wellcome Scholar in Clinical Pharmacology.