Pharmacogenetics

Interindividual variability in xenobiotic metabolism and drug response is extensive. Genetic factors might be estimated to account for about 20-40 % of the interindividual differences in drug metabolism and response. Adverse drug reactions (ADRs) occur in 7 % of all hospitalised patients and fatal ADRs cause more than 100,000 deaths annually in the US.

The costs in Sweden for ADRs can be estimated, based on calculations in the US, to 15-23 billion SEK. Pharmacogenetics aims at understanding the interindividual differences in drug response based on the knowledge about variations in genes encoding drug transporters, drug metabolising enzymes and drug targets.

In Europe a large group (about 10 %) are deficient in cytochrome P450 enzymes responsible for metabolism of about 20 % of drugs on the market and they receive too high plasma concentrations at ordinary doses and increased susceptibility for adverse drug reactions. Another outlier group, Ultrarapid metabolisers (UMs) were identified by us in 1992, where the subjects have duplicated or multiduplicated genes encoding drug metabolising enzymes.

As a result too rapid drug metabolism occurs and the subjects get no response at ordinary dosage. This encompasses 5.5 % of the European population and is a common phenomenon to non response of e.g. antidepressant therapy. In addition, the UMs form too much of the metabolites and this is a problem e.g. after codeine therapy where very high amount of morphine is formed among UMs for CYP2D6.

This has been described to cause lethality in infants as well as abdominal pain. Recently we have identified UMs for CYP2C19 and the role of this phenotype for treatment of depression and ulcer is being investigated, partly in collaboration with Clinical Pharmacology at Karolinska University Hospital, Huddinge.

We have also found interesting new gene variants of apparent great importance for development of depression. This finding would allow the development of pharmaceutical intervention. Transgenic mice models in this area are established.

In general, the research program aims at understanding the basis for interindividual differences in human drug metabolism and drug toxicity with emphasis on genetic polymorphism of the genes encoding various forms of cytochrome P450.

Factors of importance for the regulation of these enzymes are studied with emphasis on those acting on polymorphic motifs. Novel genetic variants and mechanisms for mRNA generation are identified and characterised.

The properties of the corresponding enzyme products are evaluated. The schematic basis for our research if given in Figure 1.

Figure 1. Our research projects often starts with the finding of outliers in drug therapy. Analysis of appropriate genetic variants in these patients often reveals novel variants of known genes encoding drug metabolising enzymes. The variant genes and cDNAs are expressed in heterologous systems and the functional genetic alterations are identified and characterised with respect to consequences. This allows the development of simple genetic methods to be used in the clinic to optimize drug therapy.

A specific finding has been the discovery of alleles carrying multiple gene copies causing expression of much elevated amounts of enzyme protein. This causes ultrarapid drug metabolism and no therapeutic effect at ordinary doses, and in addition highly elevated levels of metabolites that can cause adverse effects. Morphine formation after intake of codeine is one example.

Figure 2. Major interindividual differences in the rate of CYP2D6 dependent drug metabolism because of the distribution of alleles carrying 0, 1, 2, 3 or higher number of CYP2D6 gene copies in the European population. Non response of drug treatment, e.g. by antidepressants is seen commonly among ultrarapid metabolisers.

The program also encompasses the identification of new enzyme systems involved in reduction of drugs. The function and specific expression of cytochrome P450 in tumor tissue is also investigated with possible outcome for development of new drugs in cancer therapy. Results from the project can also be used for predicting effective drug treatment both with respect to the dose of the drug but also for the choice.

This is believed to be of great importance in order to reduce the costs for the society for drug treatment and for better health within a substantial fraction of the population.

At the section we also carry out research based on spin off from our pharmacogenetic investigations where we find important genes or gene variants related to disease or disease treatment. At present we are very interested in a project where we can utilize a P450 as a drug target in cancer treatment and another where we have found a gene variant highly overrepresented in depressed patients.

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