Human Molecular Genetics - Term Paper Example

Introduction The CYP2D6 enzyme is involved in the metabolism of various es of drugs. CYP2D6 polymorphism is a common occurrence, which can result in the loss of enzyme activity, and leading to lower drug efficacy, various side effects and drug-drug interactions. This essay briefly describes the CYP2D6 gene and enzyme, CYP2D6 polymorphism and related issues and how it affects breast cancer patients receiving adjuvant tamoxifen therapy. Cytochrome P450 The cytochrome P450 family of enzymes are monooxygenases located in the endoplasmic reticulum. These enzymes catalyze many reactions involved in drug metabolism and synthesis of steroids, cholesterol, and other lipids. They metabolize at least 20% of commonly prescribed drugs (Entrez Gene, 2009). CYP2D6 The CYP2D6 gene is located near two cytochrome P450 pseudogenes on chromosome 22q13.1 and it encodes a member of the cytochrome P450. Some spliced transcript variants that encodes different isoforms have also been found for the CYP2D6 gene (Entrez Gene, 2009). CYP2D6 metabolizes the following classes of drugs including: tamoxifen, beta-blockers, anti-depressants, anti-psychotics etc. As far as tamoxifen is concerned, the CYP2D6 enzyme metabolizes tamoxifen to its most active form, endoxifen. “Humans all inherit two alleles for the CYP2D6 gene, one from each parent. Each allele may be normal (designated wt) or variant type (designated vt). Thus, genotypically, an individual may be homozygous wild type (wt/wt), heterozygous (wt/vt), or homozygous variant (vt/vt). Each of these genotypes may lead to variable metabolism of drugs like tamoxifen” (Hartman & Helft, 2007.) CYP2D6 polymorphism The cause of CYP2D6 polymorphism can be attributed to single nucleotide polymorphisms (SNPs). This results in either the loss of the entire gene or loss of enzyme activity. Depending on the level of activity, CYP2D6 polymorphism can be classified into four levels: poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs) (Bernard et al., 2006.) In the majority of the population, there is expression of the EM phenotype. Poor metabolizers metabolize drugs at very slow rate; they inherit two deficient CYP2D6 alleles. As a consequence of this, drugs that are CYP2D6 substrates get accumulated, resulting in lower efficacy for drugs requiring CYP2D6 activation, greater potential for side effects and drug-drug interactions. “The UM phenotype is caused by the duplication, multiduplication, or amplification of active CYP2D6 genes, including primarily the CYP2D6*2 allele, but also involving CYP2D6*1 and others.” These people have an ultrarapid metabolism of drugs, leading to a loss of therapeutic efficacy at standard doses. In intermediate metabolizers, the metabolism of drugs activity ranges from that seen in poor metabolizers to that in extensive metabolizers. These people are heterozygous for a defective CYP2D6 allele (Bernard et al., 2006.) Incidence of CYP2D6 polymorphism In Caucasians, 1 % of the population is ultrarapid metabolizers, since they have multiple copies of the CYP2D6 gene, while 7% to 10% of the population is poor metabolizers (Hartman & Helft, 2007). In Ethiopians, 30% of the population is ultrarapid metabolizers (Nass & Moses, 2007.) Tamoxifen Tamoxifen is the most commonly prescribed Selective Estrogen Receptor Modulator (SERM). The indications for the use of tamoxifen include: hormone-receptor-positive, early-stage breast cancer after surgery/chemotherapy or radiation, and advanced (metastatic) hormone-receptor-positive disease. In addition, it is also used to reduce the risk of hormone-receptor-positive breast cancer recurrence, and to reduce the breast cancer risk in women who are at a very high risk for breast cancer (Breastcancer.org, 2009.) The side-effects of tamoxifen includes hot flashes, venous thrombosis, and endometrial cancer. The selective serotonin reuptake inhibitors (SSRIs) are inhibitors of the CYP2D6 enzyme, and are frequently given to breast cancer patients to counter some side-effects of tamoxifen therapy and to treat the associated depression in these patients (Bernard et al., 2006). In such patients who are taking SSRIs, a lesser response to tamoxifen may be observed. This is due to a lower rate of formation of the active metabolite of tamoxifen, endoxifen. Therefore, an altered tamoxifen activity and poorer clinical outcomes may be present (Hartman & Helft, 2007.) Poor metabolizers have a very low level of endoxifen production with lesser tamoxifen efficacy, and are thus, at a higher risk for the recurrence of breast cancer (Hartman & Helft, 2007.) Current molecular tools used for testing CYP2D6 polymorphisms The FDA has cleared a microarray assay called AmpliChip, in order to identify a person’s genetic variation in CYP2D6. The AmpliChip has the capability to detect 29 polymorphisms in the 2D6 gene along with any gene duplications and deletions. In addition, it can identify poor metabolizers before the start of therapy, which can prevent adverse drug reactions, and identify intermediate metabolizers and ultra-rapid metabolizers for drug adjustment prior to therapy to maximize drug efficacy (Specialty Laboratories, 2006.) Ethical issues related to genetic testing for CYP2D6 polymorphisms Some of the ethical questions being raised as far as tamoxifen therapy for breast cancer is concerned are the circumstances under which testing for CYP2D6 should be done and the circumstances under which they should avoid potent inhibitors of CYP2D6. There are concerns over the use of CYP2D6 genotyping. There are not enough prospectively validated data, and the number of patients from which results have been obtained is also small. The drawback with retrospective data is that it is not possible to exclude the possibility that some factor other than CYP2D6 genotype may be responsible for the outcomes. On the other hand, prospective trials can control such confounding factors. Considering that the benefits of adjuvant tamoxifen therapy are high, “the standards of validation for a predictive test used to determine whether or not that therapy should be provided must be high” (Hartman & Helft, 2007.) There is an ethical responsibility to adequately balance the risks and benefits so that the patients can make proper informed decisions. Therefore, it might be better to wait till such testing has prospectively proven efficacy or other proven alternatives are available (Hartman & Helft, 2007; Higgins et al., 2009.) The relevance of screening and testing for CYP2D6 polymorphisms Postmenopausal, hormone-positive breast cancer patients who are considering adjuvant tamoxifen therapy have a choice between either a 5-year aromotase inhibitor (AI) treatment or sequencing tamoxifen and an AI. Currently, both of these therapies are acceptable and widely used. Thus, by providing postmenopausal women with information about their CYP2D6 genotype, they would be able to make an informed choice about their adjuvant tamoxifen therapy as well as avoid the possibility of taking an inefficient therapy. However, such alternatives are not available for premenopausal and perimenopausal women and they do not have any proven, equivalent alternatives to tamoxifen. Hence, till more conclusive data is available, the routine performance of CYP2D6 genotyping as a predictive test for treatment decisions is not advisable for pre and perimenopausal women (Hartman & Helft, 2007). There is also concern about the very high expense involved in CYP2D6 genotyping as a predictive test, and therefore, it cannot be easily recommended (Bernard et al., 2006.) The subcommittee panel members of the FDA also could not come to a clear agreement on whether CYP2D6 genetic testing should be undertaken for patients receiving adjuvant tamoxifen (Nass & Moses, 2007) Potential role of health professional in testing for CYP2D6 polymorphisms Many genes, which are responsible for diseases, have been identified over the years. In addition, the Human Genome Project has also been completed. This has the potential to change the future of health care. Health professionals can contribute by “promoting wider public knowledge of genetic research and its implications, in fostering public debate on key issues, and in seeking clearer policies in the health sector concerning the use of genetic information about individuals” (Cullen & Marshall, 2006.) The use of AmpliChip microarray assay to identify a person’s genetic variation in CYP2D6 can help in the prediction of expected enzyme activity. This helps the physician to individualize drug therapy for each patient. Individualized drug therapy helps patients by minimizing drug dose requirements and adverse drug reactions. Conclusion The cytochrome P450 family of enzymes, located in the endoplasmic reticulum, catalyze many reactions involved in drug metabolism. The CYP2D6 enzyme is involved in the metabolism of various classes of drugs including tamoxifen, which is a Selective Estrogen Receptor Modulator used in adjuvant therapy of breast cancer. The cause of CYP2D6 polymorphism can be attributed to single nucleotide polymorphisms (SNPs) and are of four levels: poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers. Poor metabolizers have a very low level of endoxifen production with lesser tamoxifen efficacy, and are thus, at a higher risk for the recurrence of breast cancer. The AmpliChip can detect polymorphisms in the CYP2D6 gene and identify poor metabolizers before the start of therapy, which can prevent adverse drug reactions, and identify intermediate metabolizers and ultra-rapid metabolizers for drug adjustment prior to therapy to maximize drug efficacy. The use of AmpliChip helps the physician to individualize drug therapy for each patient, and thus minimize drug dose requirements and adverse drug reactions. There are concerns over the use of CYP2D6 genotyping. Currently, there are not enough prospectively validated data to justify its use, and in addition, the cost is prohibitive. References Breastcancer.org (2009). Tamoxifen. Retrieved March 31, 2009 from, http://www.breastcancer.org/treatment/hormonal/serms/tamoxifen.jsp Bernard, S, Neville, KA, Nguyen, AT, Flockhart DA (2006). Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications. The Oncologist. 11(2). 126-135. Cullen, R, Marshall, S (2006). Genetic research and genetic information: a health information professionals perspective on the benefits and risks. Health Information & Libraries Journal. 23(4): 275-282. Entrez Gene (2009). CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6. Retrieved March 31, 2009 from, http://www.ncbi.nlm.nih.gov/sites/entrez Hartman, A, Helft, P (2007). The ethics of CYP2D6 testing for patients considering tamoxifen. Breast Cancer Research. 9 (2). Higgins MJ, Rae JM, Flockhart DA, Hayes DF, Stearns V (2009). Pharmacogenetics of tamoxifen: who should undergo CYP2D6 genetic testing? J Natl Compr Canc Netw. 7(2): 203-13. Specialty Laboratories (2006). AmpliChip™ CYP450. Retrieved March 31, 2009 from, www.specialtylabs.com/education/download_PDF/AmpliChip.pdf Nass, SJ, Moses, HL, 2007. Cancer biomarkers: the promises and challenges of improving detection and treatment. National Academies Press. Read More