Pharmacogenetics and thiopurine metabolism

It is well known that drugs can have different effects in patients with the same disease despite the fact that they receive the same dose of the drug. One important reason for this is genetic differences in the capacity of drug metabolizing enzymes. Large differences in the levels of metabolizing enzymes within a population are due to the existence of single nucleotide polymorphisms (SNPs) in the genes encoding metabolizing enzymes.

New and better ways of avoiding side effects

The purpose of our research is to find new and better ways of avoiding unnecessary and life treating side effects during treatment with anticancer agents. My research focuses on the thiopurines. Thiopurines are used for the treatment of acute lymphoblastic leukemia in children and also inflammatory bowel diseases in adults.

The thiopurines are metabolized in the body by a complex set of enzymes. One important enzyme is thiopurine methyltransferase (TPMT). This enzyme is polymorphic, meaning that 90 % of the population has high/normal activity, 9 % have intermediate activity, and 1/300 has almost no activity at all. Individuals lacking TPMT have an increased risk to develop severe side effects if treated with conventional thiopurine doses. The decreased activity is due to the existence of SNPs in the TPMT gene. The knowledge of the genetic regulation of the thiopurine metabolism has created new possibilities to individualize the treatment and the focus has since the 1980s been on TPMT. 

TPMT nomenclature committee - Naming of genetic variants in the TPMT gene

Together with international partners, I run the TPMT nomenclature committee, which works with the mapping and naming of genetic variants in the TPMT gene. Please see our website TPMT nomenclature committee, for more information. A paper was published in 2013 describing the work of the TPMT nomenclature committee (Appell ML et al., 2013 Pharmacogenetics and Genomics 2013, 23:242-248).

In my research projects I am trying to understand the genetic regulation of the TPMT enzyme. I am also interested in other enzymes in the thiopurine metabolism and in other factors that could influence the metabolism. We also study new genetic variants that we find in our patients.

In our research, cancer cell lines are important tools. In these cells we can investigate what happens when we turn off or turn on a gene involved in thiopurine metabolism. We can treat the cells with drugs and see the effect of different combinations of drugs.

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