Editorial

Tailored Medicine: Pharmogenomics and Pharmacogenetics

Susana B. Bravo, Jorge E. Caminos, Javier Hernando Eslava Schmalbach

PhD, Departamento de Fisiología, Escuela de Medicina-Instituto de Investigaciones Sanitarias (IDIS), Universidad de Santiago de Compostela, Santiago de Compostela, España. Correo electrónico: susanabelen.bravo@usc.es

PhD, Departamento de Fisiología. Facultad de Medicina, Universidad Nacional de Colombia. Correspondencia: Cra. 30 No. 45-03 Facultad de Medicina. Of. 205. Universidad Nacional de Colombia, Bogotá, Colombia. Correo electrónico: jecaminosp@unal.edu.co

PhD, Instituto de Investigaciones Clínicas, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia. Correo electrónico: jheslavas@bt.unal.edu.co

Recibido: junio 16 de 2011. Enviado para modificaciones: junio 21 de 2011. Aceptado: junio 23 de 2011.

The human genome program, the breakthroughs and developments of the various “omics”, with the support of translational medicine, have driven knowledge and progress with regards to many of the molecular mechanisms of human physiology and pathology. Based on this knowledge there us numerous evidence showing that drug therapy can be individualized based on the studies of the human genome variations, considering that only between 30 % to 60 % of the patients have a common answer to those therapies (1).

The Human Variome Project (HVP) studies the simple nucleotide polymorphisms (SNP) generated, to a large extent, by the effect of evolution and give rise to the variability of the genotype in the population; these variations may have implications in the adaptation of the species to a particular environment or, on the contrary, may become the cause for many diseases (2). These variations are of great biomedical interest for studying, among other areas, the different genes associated to the drug metabolizing enzymes.

The pharmacogenomis^* database has been available since the year 2000 and provides information on the human genome variation and the response to drugs (3). Tailoring treatment based on these variations has implications in terms of the adverse effects to certain medicines, hospitalization time and the number of drug-related deaths (4). These studies have become some of the main breakthroughs and promises for understanding, diagnosing and treating many diseases.

The P450 cytochrome super family of enzymes is one of the key targets of analysis in pharmacogenomics (5). These are the enzymes responsible for 75 % to 80 % of Phase I metabolism and of 75 % to 80 % of the clearance of the various drugs used in the clinic. These enzymes are coded by 57 types of genes and are involved in the metabolism of exogenous substances, including drugs. The characterization of the polymorphisms of the various CPY family enzymes is one of the pillars of personalized medicine as a concept, which provides the foundation for selecting the type of drug, the dose and any adjustments thereof.

The different variations in the genotype of the CPY genes give rise to the four phenotypes of metabolizers known as ultrarapid, extensive, intermediate and slow. Another key biomedical target is the arilamine N-acetiytransferase enzyme that becomes relevant to pharmacogenetics due to the different polymorphisms described, which is related to slow/fast acetylation phenotypes and with the high toxicity impact of different drugs. Moreover, there are pharmacogenetic databases of various membrane transporters showing their genetic variation and the variation-associated response to different drugs** (1).

It has been know for over 50 years that in most cases genetic factors impact the individual response to the pharmacological agents used in anesthesia (6,7). The opioids used for many years in anesthesia and acute and chronic pain, are an example of the variations in terms of the dose used for individual patients. To a large extent, these variations have been explained on the basis of genetic heterogeneity that impacts the pharmacokinetics and pharmacodynamics of these drugs. Opioid μ-receptors mediate the neuromodulation processes through the inhibitory protein-G (Gi) mediated signals.

Different μ-receptor polymorphisms of the opioid receptor have been described that are associated to the different response of patients to opioids. One of the known polymorphisms or SNP of the μ-receptor is c.118A.G (A118G), with an allele frequency of 2 % - 40%, depending on ethnicity. It may be possible that our population requires massive studies –consistent with governmental policies– for developing databases of our genetic variation with respect to the genes associated to drug metabolism and transport. Such government policies are being developed by many countries around the world, with high expectations to provide the best treatment to patients.

In 1940, Conrad Hal Waddington, professor at Cambridge University, defined epigenetics as the causal interaction of the molecular components that modulate the expression of a genotype into a particular phenotype (8,9). The differential expression of a subgroup of proteins from a total of around 20.300 into approximately 230 cell types described in a human organism, are related to the regulation of epigenetic changes mainly associated to the histone code and the methylation pattern of the CpG islets from the different promoters that govern the gene expression (8,9).

Thus, epigenetics is actually defined as: “the study of changes in the gene function that are mithotically and/or meiothically inherited and entail changes in the DNA sequence” (10). Furthermore, the Human Epigenome Project (HEP), a public-private consortium proposal, seeks to identify and classify the pattern of methylation of every gene in most tissues, throughout the human genome (10).

Epigenetic changes are mostly reversible changes that vary with age, play an important role in silencing and expressing of coding and noncoding regions. These are associated to histone variants, post-transductional changes in some histone amino acids, related to changes in the methylation, acethylation, sumoilation, phosphorilation, ubiquitination, and ADP-ribosylatión patterns, among others, in addition to covalent changes with methyl groups in the cytokines of the CpG islets (11).

It has been known that the regions that promote the silenced genes have more methylated cytokines when compared to active gene modifications and are thus involved in transcriptional repression (11). These epigenetic factors affect the expression of metabolizing and drug-transporting enzymes, the expression of nuclear receptors that influence the response of the various drugs.

The epigenetic patterns may be maintained or deleted between generations and these may have beneficial or detrimental impacts among the population; hence their clinical relevance. Breakthroughs in epigenetics and epigenomics research have had a significant impact in pharmacology and, consequently, in the development of an area called pharmacoepigenetics devoted to studying the epigenenetic basis for the diverse response to drugs and pharmacoepigenomics (9,10).

The implications of the changes in epigenetic profiles and their association to diseases such as cancer, coronary disease, CVA and diabetes have been clearly demonstrated. Different compounds have been used, mainly in cancer studies, such as DNA methylation inhibitors and histone deacetylase enzyme inhibitors, including the azacytidine compounds, decitabine, vorinostat and romidepsin. Pro or antinociceptive gene expression can be silenced via epigenetic mechanisms. Moreover, it is through epigenetic mechanisms that the expression of CYP enzymes is regulated and many of these are associated to the metabolism of analgesics.

Pharmaepigenomic approaches are particularly useful when the pharmacogenetics or the variation in the genome sequence is unable to explain drug response variability. Pharmacoepigenomics studies the response variations of individuals to drugs on the basis of epigenomics, drug-related expression profile changes, the mechanism of action and any adverse reactions to drugs, in addition to the search for new therapeutic targets.

Studies are particularly focused to learning about the epigenetic regulation of the enzymes involved in the metabolism of drugs and of other proteins affecting drug response. Thus, it is crucial to highlight the importance of strengthening massive network-based programs on biomedical research, aimed at developing our own pharmacogenomics and pharmacoepigenomics databases. Evidently, there are several groups in the country working in this direction, however these must be strengthened via macro programs to make them more visible versus the needs of the State in the area of healthcare.

The differential response of patients to anesthetic agents, to critical care medicines, to painkillers, among others, are according to these concepts also related to the individual metabolism that is genetically programmed in every patient using these drugs. This indeed a novel area of research for these disciplines and it must be increasingly fostered towards a more rational medical practice (11-13).

This is then an invitation to further encourage the inclusion of pharmacogenomics and pharmacogenetics in research and education programs dealing with the variability of our patient's individual response to treatment.

COMMENTS

^* PharmGKB, véase en http://www.pharmgkb.org/.

REFERENCES

1. Sim SC, Altman RB, Ingelman-Sundberg M. Databases in the area of pharmacogenetics. Hum Mutat. 2011;32:526-31.

2. Oetting WS. Clinical genetics & human genome variation: the 2008 Human Genome Variation Society scientific meeting. Hum Mutat. 2009;30:852-6.

3. Pinto N, Dolan ME. Clinically relevant genetic variations in drug metabolizing enzymes. Curr Drug Metab. 2011;12:487-97.

4. Boone PM, Wiszniewski W, Lupski JR. Genomic medicine and neurological disease. Hum Genet. 2011 [Epub ahead of print].

5. Johansson I, Ingelman-Sundberg M. Genetic polymorphism and toxicology-with emphasis on cytochrome p450. Toxicol Sci. 2011;120:1-13.

6. Searle R, Hopkins PM. Pharmacogenomic variability and anaesthesia. Br J Anaesth. 2009;103:14-25.

7. Restrepo JG, García-Martín E, Martínez C, et al. Polymorphic drug metabolism in anaesthesia. Curr Drug Metab. 2009;10:236-46.

8. Carlquist JF, Anderson JL. Pharmacogenetic mechanisms underlying unanticipated drug responses. Discov Med. 2011;11:469-78.

9. Gómez A, Ingelman-Sundberg M. Pharmacoepigenetics: its role in interindividual differences in drug response. Clin Pharmacol Ther. 2009;85:426-30.

10. Baer-Dubowska W, Majchrzak-Celinska A, Cichocki M. Pharmocoepigenetics: a new approach to predicting individual drug responses and targeting new drugs. Pharmacol Rep. 2011;63:293-304.

11. Martín-Subero JI, Esteller M. Profiling epigenetic alterations in disease. Adv Exp Med Biol. 2011;711: 162-77.

12. Searle R, Hopkins PM. Pharmacogenomic variability and anaesthesia. Br J Anaesth. 2009;103:14-25.

13. Restrepo JG, García-Martín E, Martínez C, et al. Polymorphic drug metabolism in anaesthesia. Curr Drug Metab. 2009;10:236-46.