Individual and variable drug reactions are a significant problem, not only in therapies of existing diseases, but also in clinical studies and testing of potential new drugs. The variations range from a failure of the drug and consequently also of the therapy, to a serious drug reactions. Possible causes of these unwanted drug reactions are normal habits of the patient (smoking, drinking,…) but also interactions between different ingested drugs and also the genetic disposition. Today these drug interactions are one of the most often occurring treatment complications in the industrial countries and they are the sixth most common causes of death.

It has longer been known, that the different tolerance or efficiency of drugs is caused genetically. The pharmacogenomics< deals with the searching of clinically relevant and genetic factors in the whole genome. The pharmacogenetics identifies genetic variants and have a look at the tolerance. In focus are changes in the DNA-sequence of enzymes within the drug metabolism, mainly representatives of the so called Cytochrome P450-Family, the Multiple-Drug-Resistance-1 (MDR-1)transporter and the N-Acetyltransferase 2 (NAT2) and the Dihydropyrimidin-Dehydrogenase (DPD).

Cytochrome P450

The heterogeneous group of the cytochromes includes enzymes, which are catalysing oxidative biotransformations of different xenobiotics (drugs). They have an interindividual variance, that causes a changed enzyme functionality. This change is either a faster or a slower catalysis / effect of the respective drug.

Two out of three drugs are metabolized by the CYP3A4 isoform, the rest by the enzymatic system CYP2D6, CYP2C9 and CYP2C19.

CYP3A4 is the most expressed isoform in the liver. CYP3A4 is known, that this protein is inhibited by a lot of other substances (grapefruit juice for example) or is induced by others. That is important, if there are other drugs are taken at the same time with this medication.

CYP2D6 is involved at the metabolism of about 20 percent of the common drugs, like psychotropics, neuroleptics and beta blocker. Interesting is this enzyme because of efficiency and tolerance of tamoxifen, a selective estrogen receptor modulator, which is taken against breast cancer. Variants of CYP2D6 are causing a deficit (no metabolism, danger, because of side effects or no effect), a restriction (delayed metabolism, side effects) or highly increasing activity of the enzyme (too fast metabolism, dager of no effect).

CYP2C9 and CYP2C19 take part at about15% of the drug metabolisms, but their importance is much higher. CYP2C9 is involved in the oxidative metabolism of drugs and anti-diabetics, and also derivatives of coumarin and common drugs like ibuprofen and warfarin. The CYP2C9 gene is high polymorphic, more than 50 variants are described in literature. Some of them cause a strong reduced enzyme activity.

CYP2C19 metabolized substrates like antidepressants, neuroleptics and also proton pump inhibitors, which are successfully used for ulcer prophylaxis. The metabolism way with CYP2C19 is also an alternative for some substrates of CYP2D6. Genetic variances in CYP2C19 causes a loss, restriction or increasing of the enzyme activity. This results in different metabolism velocities.

Multiple Drug Resistance-1

One more important genetic factor, that has an important role in the drug metabolism is the MDR-1 gene. This gene product is the so called P-Glycoprotein (PgP), a trans membrane protein, which effects the active membrane transportation. On the hand PgP causes the excretion of toxins from the cell, because of that it is a big handicap for the effect of cytostatics. MDR-1 has a wide substrate spectrum, with a lot of substances of the chemotherapy: cisplatin, vinca-alkaloids, imatinib, texane and so on. A point mutation in the area of MDR-1 cause a lower expression of the transportation protein and this effects, that the toxic metabolites enriching in the cell.

Recommended tests:
Cytochrom P450
MDR1
NAT2
DPD

Literature
Wolf RC, Smith G, Smith RL. Pharmacogenetics. BMJ; 320: 987-990, 2000
Wellmann A (1999), Auf dem Weg zu individuell wirksamen Arzneien. Dtsch. Ärztebl. Jg. 96, Heft 40, 1999
Evans WE, Relling MV. Science, Vol. 286 no. 5439 pp. 487-491, 1999
Evans WE, Relling MV. Nature, 429 (6990):464-8, 2004
Pauli-Magnus C, Pharmacogenomics, 85: Nr 37, pp. 1963-1974, 2004


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