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CYP2D6 and the oestrogen receptor

The medicinal adjuvant therapy of breast cancer is a good example of how important it is being aware that different patients metabolise drugs differently. This knowledge plays a key role in the prescription of effective drugs at the correct dose and in preventing adverse reactions and interactions with concomitant drugs.

Breast cancer is still the most frequent cancer in women in Germany, although the number of breast cancer-related deaths has decreased considerably over the last few years, particularly in pre-menopausal women. Between 1989 and 2006, the mortality rate of pre-menopausal women with breast cancer decreased by around 46 per cent. There are two main factors that have led to this positive development: on the one hand, breast cancer screening involving mammography has been put in place to improve the early identification of cancerous lesions; on the other hand, breast cancer therapy has considerably improved and more effective drugs have become available.

Cases where tamoxifen must not be used to treat breast cancer

Tamoxifen - chemical structure © Jarasch

It has been known for quite some time that breast cancer patients respond differently to breast cancer drugs. It is widely assumed that the development of breast cancer is associated with hormones, in particular the female sex hormone oestrogen, and that it can also be linked to progesterone. Oestrogen-receptor-positive tumours, i.e. tumours that require oestrogen to grow, can be blocked by antihormones that suppress the oestrogen receptor. One of the most common antihormones used for this purpose is tamoxifen, which was developed by ICI Pharmaceuticals (now AstraZeneca) and is mainly used in the adjuvant therapy of oestrogen-receptor positive breast cancer, i.e. therapy to prevent the development of relapses or metastases that complements primary treatment in the form of surgery, radiology or chemotherapy. Tamoxifen must not be given to women with oestrogen receptor-negative tumours.

On 3rd November 2010, the German Federal Institute of Drugs and Medical Devices (BfArM), the organisation responsible for drug safety in Germany, published a warning that tamoxifen must not be taken concomitantly with so-called CYP2D6 inhibitors, including frequently prescribed antidepressants such as paroxetin (Seroxat), fluoxetin (Prozac) and bupropion, as well as drugs such as the cardiac drug chinidin or the drug cinacalcet used to treat parathyroid diseases that act on ion channels.

CYP2D6 refers to the enzyme cytochrome P450 type 2D6 that plays a pivotal role in the metabolism of many prescription drugs, including cardiovascular drugs (beta blockers and antiarrhythmic drugs), numerous antidepressants and neuroleptics (antipsychotic drugs) and strong pain killers (opiods). These compounds are mainly degraded in the liver by way of CYP2D6 catalysis or, in the case of a prodrug such as codein, they are activated. Tamoxifen is a prodrug that is converted into its active form, endoxifen, by CYP2D6.

Limits in the ability to predict the efficacy of drugs

The ability to predict the safety and efficacy of drugs (pharmacovigilance) has its limits when patients are concomitantly taking drugs to treat other indications, where each drug exerts different effects in different organs and where the metabolism of drugs depends on the genetic disposition of the individual patient. The situation becomes even more complicated when drugs interfere with the complex, finely tuned network of hormone-controlled signalling chains. Despite all these complications, the BfArM is making every effort to identify undesired adverse drug reactions as early as possible in order to make patients aware of potential dangers and risks. In order to achieve this, the BfArM is collecting experiences and observations from hospitals and clinics. Forms to report potential adverse drug reactions can be downloaded from www.bfarm.de.

Prof. Dr. Doris Mayer © DKFZ

Prof. Dr. Doris Mayer runs a workgroup on "Hormones and Signal Transduction" at the German Cancer Research Center in Heidelberg, which is investigating the influence of hormones on the development of cancers of the breast, prostate and the liver. The researchers' studies have shown that the function of the oestrogen receptor, which is targeted by tamoxifen, is regulated by a special protein kinase (glycogen synthase kinase 3) in breast cancer cells. Glycogen synthase kinase 3 itself is activated by another protein kinase known as PKCdelta. Glycogen synthase is a key enzyme of the glucose metabolism that is regulated by insulin and the insulin-like growth factor (IGF). The interactions between the IGF signalling pathway and the oestrogen-receptor signalling pathway are being investigated by the Heidelberg researchers on the basis that "to be able to interfere with the process of receptor activation when treating cancer it is necessary to know what interaction occurs between the growth factor and the steroid hormone". A medical intervention needs to take into account the complex network of signalling chains and potential  adverse drug reactions. In cooperation with the BfArM, Mayer has investigated the influence of insulin analogues on the glucose metabolism and their potential carcinogenic effects.

Paradigm example of personalised medicine

Three-dimensional model of a cytochrome P450 protein; the haeme component which is responsible for the colour of blood is shown in the centre of the model © Jarasch

The members of the cytochrome P450 protein family, which has at least 36 different known human enzymes, are paradigm examples of drugs whose effect depends on the genetic make-up of individuals. The cytochrome P450 enzymes play a key role in phase I of biotransformation, as they ensure that oxygen is incorporated into the fat-soluble substances to be degraded (the majority of drugs). In a second biotransformation step, a water-soluble functional group is incorporated into the molecule, thereby facilitating degradation and excretion.

CYP2D6 is a highly polymorphic gene of which around 70 different CYP2D6 gene variants are known; 16 of these genes are associated with absent CYP2D6 enzyme activity. People with these kinds of gene variants only metabolise drugs like the aforementioned antidepressants very slowly (by way of other cytochrome P450 enzymes), with the result that the various substances accumulate in the patient and lead to severe side effects. In contrast, tamoxifen, which is a prodrug and therefore only converted into its active, effective form by way of CYP2D6-catalysed biotransformation, has no effect whatsoever when given in normal doses to carriers of one of the 16 variants.

Patients are classified into four metaboliser groups according to the effectiveness of the genetic CYP variants:

  • Poor metabolisers with two mutated CYP genes that lead to the complete loss of enzyme activity;
  • Intermediate metabolisers who have one CYP gene with reduced enzyme activity;
  • Extensive metabolisers with one or two functional genes;
  • Ultra-metabolisers with three or more functional gene copies.

Ultra-metabolisers degrade drugs so rapidly that justifiable drug dosages are unable to achieve a strong enough effect.

The frequencies of the individual metaboliser groups vary considerably in different population groups. In Germany, around three per cent of people are ultra-metabolisers with several functional CYP2D6 gene copies, in North Africa this figure can be as high as 20 to 29 per cent. While seven per cent of all Europeans are characterised as poor metabolisers, only one to two per cent of Asians fall into this category.

The importance of genotyping

It goes without saying that the treatment of breast cancer patients with drugs that are metabolised by way of the CYP2D6 enzyme system needs to take into account the tumour’s hormone receptor state as well as the patient’s metaboliser characteristics in order to prevent unwanted drug reactions.

Roche Diagnostics markets its proprietary AmpliChip® CYP450 test for the routine pharmacogenetic diagnosis of the CYP2D6 enzyme system. Roche Diagnostics’ test is the first ever genetic test that has been cleared for the detection of CYP450 polymorphisms using biochips. It works as follows: DNA segments are extracted from a patient’s blood sample, amplified using PCR and applied to a biochip containing more than 15,000 different oligonucleotide probes. The AmpliChip® CYP450 test can differentiate between 29 different variants of the CYP2D6 gene (as well as two variants of another cytochrome P450 gene, i.e. the CYP2C19 gene) and it is also able to detect duplications or deletions of the gene variants, thereby making it possible to correctly predict whether a certain patient is an ultra- or poor mebaboliser and so adjust the drug dose to the requirements of that patient, or avoid using the drug altogether if the patient is unable to metabolise it.

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