The terms pharmacogenomics and pharmacogenetics tend to be used interchangeably, and a precise, consensus definition of either remains elusive. Pharmacogenetics is generally regarded as the study of genetic variation that gives rise to differing response to drugs, while pharmacogenomics is the broader application of genomic technologies to new drug discovery and further characterization of older drugs. Pharmacogenetics considers one or at most a few genes of interest, while pharmacogenomics considers the entire genome. Much of current clinical interest is at the level of pharmacogenetics, involving variation in genes involved in drug metabolism with a particular emphasis on improving drug safety. Pharmacogenomics is the branch of pharmaceutics which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drugs efficacy or toxicity. ... Pharmacogenomics is the branch of pharmaceutics which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drugs efficacy or toxicity. ... Pharmacogenomics is the branch of pharmaceutics which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drugs efficacy or toxicity. ... Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. ...

Pharmacogenetics and adverse drug reactions

The first observations of genetic variation in drug response date from the 1950s, involving the muscle relaxant suxamethonium chloride, and drugs metabolized by N-acetyltransferase. One in 3500 Caucasians has less efficient variant of the enzyme (butyrylcholinesterase) that metabolizes suxamethonium chloride. As a consequence, the drug’s effect is prolonged, with slower recovery from surgical paralysis. Variation in the N-acetyltransferase gene divides people into “slow acetylators” and “fast acetylators”, with very different half-lives and blood concentrations of such important drugs as isoniazid (antituberculosis) and procainamide (antiarrhythmic). Suxamethonium chloride (also known as succinylcholine, or scoline) is a white crystalline substance, it is odourless and highly soluble in water. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... Isoniazid (also called isonicotinyl hydrazine or isonicotinic acid hydrazide); abbreviated INH or just H. Isoniazid is a first-line antituberculous medication used in the prevention and treatment of tuberculosis. ... Procainamide (trade name Pronestyl®) is a pharmaceutical antiarrhythmic agent used for the medical treatment of cardiac arrhythmias, classified by the Vaughan Williams classification system as class Ia. ...

One of the earliest tests for a genetic variation resulting in a clinically important consequence was on the enzyme thiopurine methyltransferase (TPMT). TPMT metabolizes 6-mercaptopurine and azathioprine, two drugs used in a range of indications, from childhood leukemia to autoimmune diseases. In people with a deficiency in TPMT, metabolism must proceed by other pathways, one of which leads to a metabolite that is toxic to the bone marrow; these people are at risk of a potentially fatal bone marrow suppression. In 85-90% of affected people, this deficiency results from one of three variant alleles. One in 300 people have two variant alleles; these people need only 6-10% of the standard dose of the drug, and, if treated with the full dose, will develop severe bone marrow suppression. For them, genotype predicts clinical outcome, a prerequisite for an effective pharmacogenetic test. Around 10% of people are heterozygous and produce a reduced quantity of functional enzyme. Overall, they are at greater risk of adverse effects, although as individuals their genotype is not necessarily predictive of their clinical outcome, which makes the interpretation of a clinical test difficult. Recent research suggests that children who are heterozygous may have a better response to treatment, which raises whether people who have two wild-type alleles could tolerate a higher therapeutic dose. Thiopurine methyltransferase, drawn from PDB 2BZG. Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme (EC 2. ... Mercaptopurine (also called 6-MP or by its brand name Purinethol®) is an immunosuppressive drug used to treat leukemia. ... Azathioprine is a chemotherapy drug, now rarely used for chemotherapy but more for immunosuppression in organ transplantation, autoimmune disease such as rheumatoid arthritis or inflammatory bowel disease such as Crohns disease. ... Leukemia (or leukaemia; see spelling differences) is a cancer of the blood or bone marrow characterized by an abnormal proliferation of blood cells, usually white blood cells (leukocytes). ... Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. ... Bone marrow suppression is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine. ... An allele is any one of a number of alternative forms of the same gene occupying a given locus (position) on a chromosome. ... The genotype is the specific genetic makeup (the specific genome) of an individual, in the form of DNA. Together with the environmental variation that influences the individual, it codes for the phenotype of that individual. ... Heterozygote cells are diploid or polyploid and have different alleles at a locus (position) on homologous chromosomes. ...

The US Food and Drug Administration (FDA) have recently deliberated the inclusion of a recommendation for testing for TPMT deficiency to the prescribing information for 6-mercaptopurine and azathioprine. Hitherto the information has carried the warning that inherited deficiency of the enzyme could increase the risk of severe bone marrow suppression. Now it will carry the recommendation that people who develop bone marrow suppression while receiving 6-mercaptopurine or azathioprine be tested for TPMT deficiency. The Food and Drug Administration (FDA) is an agency of the United States Department of Health and Human Services and is responsible for regulating food (humans and animal), dietary supplements, drugs (human and animal), cosmetics, medical devices (human and animal) and radiation emitting devices (including non-medical devices), biologics, and... Mercaptopurine (also called 6-MP or by its brand name Purinethol®) is an immunosuppressive drug used to treat leukemia. ... Azathioprine is a chemotherapy drug, now rarely used for chemotherapy but more for immunosuppression in organ transplantation, autoimmune disease such as rheumatoid arthritis or inflammatory bowel disease such as Crohns disease. ...

Variation in TPMT affects a small proportion of people, though seriously. As part of the inborn system for clearing the body of xenobiotics, the cytochrome P450 oxidases (CYP450) are heavily involved in drug metabolism, and variations in CYP450s affect large populations. Comparisons of the list of drugs most commonly implicated in adverse drug reactions with the list of metabolizing enzymes with known polymorphisms found that drugs commonly involved in adverse drug reactions were also those that were metabolized by enzymes with known polymorphisms (see Phillips, 2001). One member of the CYP450 superfamily, CYP2D6, now has over 75 known allelic variations, some of which lead to no activity, and some to enhanced activity. An estimated 29% of people in parts of East Africa may have multiple copies of the gene, and will therefore not be adequately treated with standard doses of drugs such as the painkiller codeine (which is activated by the enzyme). A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. ... Cytochrome P450 Oxidase (CYP2E1) Cytochrome P450 oxidase (commonly abbreviated CYP) is a generic term for a large number of related, but distinct, oxidative enzymes (EC 1. ... Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. ... Cytochrome P450 2D6 (abbreviated CYP2D6, EC 1. ...

References

• Abbott A. With your genes? Take one of these, three times a day. Nature 2003;425:760-762.
• Evans WE and McLeod HL. Pharmacogenomics – Drug Disposition, Drug Targets, and Side Effects. New Engl J Med 2003;348:358-349.
• Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA 2001;286:2270-2279.
• Weinshilboum R. Inheritance and Drug Response. New Engl J Med 2003; 348:529-537.

See also

• Genomics
  • Chemogenomics
  • Structural genomics
  • Pharmacogenomics
  • Toxicogenomics

Genomics is the study of an organisms genome and the use of the genes. ... Chemogenomics can be defined as a genomic response to chemical compounds. ... Structural genomics or structural bioinformatics refers to the analysis of macromolecular structure particularly proteins. ... Pharmacogenomics is the branch of pharmaceutics which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drugs efficacy or toxicity. ... Toxicogenomics is a form of analysis by which the activity of a particular toxin or chemical substance on living tissue can be identified based upon a profiling of its known effects on genetic material. ...

External links

• The Pharmacogenetics Portal
• Pharmacogenomics: Medicine and the new genetics from the Human Genome Project
• The Pharmacogenomics Journal
• PharmGKB The Pharmacogenetics and Pharmacogenomics Knowledge Base, a free online tool for Pharmacogenetics research
• The pharmacogenetics Wikibase
• DNAVision: an official laboratory for pharmacogenetic testing