Pharmacogenomics And The Pharmaceutical Industry Biology Essay

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Pharmacogenomics is the study of the genetic basis for the differences between individuals in response to drugs in order to tailor drug prescriptions to individual genotype. Optimum dose requirements for many drugs are known to vary among individuals.

It is the variations shown when the human genome affect the response to different types of medications earlier called "pharmacogenetics" was obtained from the terms "pharmacology" and "genetics" to indicate the intersection of genetics and pharmaceuticals Significance: The

sequencing of the genome and introduction of newer technologies can is easily possible to analyze multiple genes continuously not individually. It combines traditional pharmaceutical sciences such as biochemistry with annotated knowledge of genes and mono nucleotide polymorphs. Inter individual variability can be studied in drug response and combines many different fields like genetics , toxicology, pharmaceutics, population biology, statistics, genomics, pharmacology. For pharmacists it helps to find how the patient may respond to drug with the help of genetic test.

Pharmacogenomics studies:

Early Pharmacogenomics were based on familial studies of highly recurrent familial diseases. But currently Pharmacogenomics involve genetic association studies, which are more appropriate for the study of complex traits involving multiple loci. The history of Pharmacogenomics studies can be split into three generations. First generation studies examined a few candidate genes for which likely deleterious alleles and their biological consequences had been previously identified. Second generation studies, corresponding to present technology. Third generation studies will be genome-wide association studies. These second and third generation studies are and will be based on high density maps of markers, such as single nucleotide polymorphisms (SNPs, pronounced snips).Several private companies such as Celera, Curagen and Genset are currently developing high density SNP maps that they plan to use in genome wide association studies.

The SNP consortium, a non profit organization founded in April 1999 by the welcome trust and 10 large pharmaceutical companies, has set out to find and map 300,000 of the most common SNPs in the human genome. It is expected that the availability of this information will accelerate the development of Pharmacogenomics and its integration in drug research and development.

The development of Pharmacogenomic studies has been hampered by the fact that pharmaceutical companies have only recently started collecting, on a systematic basis, DNA samples from individuals who were enrolled in clinical trials.

In Genetic variations and drug efficacy Asthma provides a good example of the use of Pharmacogenomics in studying drug efficacy and toxicity.5-Lipooxygenase (5-LO) and the beta 2 adrenergic receptor are targets of anti asthma-drugs. For both of these targets gene polymorphisms were shown to influence drug efficacy.

In Genetic variations and drug toxicity Drug metabolizing enzymes are known to influence drug toxicity. The main drug metabolizing enzymes are cytochrome P450s (CYPs), for which genetic variations are known to influence drug toxicity and efficacy. Genset, using SNP-based association studies, recently found that this liver toxicity is associated with haplotypes for two liver drug metabolizing enzymes. Moreover 5-Fluorouracyl (5-FU) is widely used in chemotherapy to treat a number of cancers.

In Genetic variations and pathogenic microorganisms Pharmacogenomics is applied to study the therapeutic response of microorganisms and their hosts, in order to understand and overcome decreased sensitivity to drugs.

Pharmacogenomics and the pharmaceutical industry: In pharmaceutical industry Pharmacogenomics could be essential in speeding up the international approval of drugs that are already marketed in some countries like Japan; ethnic difference in drug response can be correlated with polymorphic drug metabolism enzymes when deleterious alleles have been identified.

Recently FDA stated that companies aiming to market drugs with narrow therapeutic indexes may find delays in approval increasingly common if they fail to submit Pharmacogenomic data pertaining to drug toxicity.

Pharmacogenomics can be a way to accelerate drug discovery and development, maximize the odds for drug registration as well as improve drug positioning.

In preclinical development, Pharmacogenomics can help pharmaceutical companies select better drug candidates by determining early on if a candidate is highly influenced by gene polymorphisms, thus reducing the risk of failure due to variable efficacy.

In future it can be said that Pharmacogenomics will allow not only individual prediction of drug efficacy and toxicity, but also the development of innovative, active and safe drugs.

References

Caporaso N., Goldstein A. Cancer genes-single and susceptibility-

exposing the difference. Pharmacogenetics, 5: 59-63, 1995.

Drews, J.S. and Ryser. S. (1996). reflections on the productivity of pharmaceutical R&D.. Innovation deficit revisited 30 (1), 97-108.

Floris A. de Jong, Maja J.A. de Jonge,Jaap Verweij, Ron H.J. Mathijssen . (2006). cancer letters. Role of pharmacogenetics in irinotecan therapy. 234 (1), 90-106.

P.Peet, and P. Bey. (2001). Pharmacogenomics. challenges and Opportunities. 6 (10), 495-498.

Ronald M. Norton. (2001). Clinical pharmacogenomics. applications in pharmaceutical R&D. 6 (1), 185.

Cytochrome P450 enzymes are diverse oxygenation catalysts that are found throughout nature.

The cytochrome P450 superfamily is a large and diverse group of enzymes. Cytochromes P450 (CYPs) belong to the superfamily of proteins containing a heme factor and, therefore are hemo proteins.

CYPs use a variety of small and large molecules as substrates in enzymatic reactions.

Human CYPs are primarily membrane-associated proteins, located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. CYPs metabolize thousands of endogenousand exogenous chemicals. Some CYPs metabolize only one (or a very few) substrates, such as CYP19 (aromatase), while others may metabolize multiple substrates. Both of these characteristics account for their central importance in medicine.

The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances such as drugs and other toxic chemicals. CYPs are the major enzymes involved in drug metabolism and bioactivation, 

The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into an organic substrate (RH) while the other oxygen atom is reduced to water:

RH + O2 + 2H+ + 2e- → ROH + H2O

Cytochrome P450 enzymes are present in most tissues of the body, and play important roles in hormone synthesis and breakdown cholesterol synthesis, and vitamin D metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, including drugs and products of endogenous metabolism such as bilirubin, principally in the liver

In general terms, drug metabolizing reactions can be divided into two broad groups-Phase 1 reactions, which involve chemical alteration of drug structure (e.g., by oxidation, reduction or hydrolysis); and Phase 2 reactions, in which the drug molecule is conjugated .CYP450 enzymes participate in multiple metabolic pathways for a wide range of structurally different compounds; for example, the two major CYP450 enzymes, CYP3A4 and -2D6, are involved in dealkylation, hydroxylation, dehalogenation, dehydration, and nitro reduction processes. In general, the result of all these Phase I metabolic processes is the conversion of drugs into more polar water-soluble compounds which can be more easily conjugated and/or excreted from the body. The involvement or relative contribution of Phase I and/or Phase 2 reactions to the metabolism of drugs can differ substantially, depending on the structures of individual compounds.

Cytochrome P450 enzymes show extensive structural polymorphism.The cytochromes involved in the metabolism are mainly monooxygenases that involved in from the steroid and fatty acid biosynthesis.

Function:

CYP 1, 2A, 2B, 2C, 2D, 2E, 3 metabolismus of xenobiotica

CYP 2G1, 7, 8B1, 11, 17, 19, 21, 27A1, 46, 51 steroid metabolism

CYP 2J2, 4, 5, 8A1 fatty acid metabolism

CYP 24 (vitamine D), 26 (retinoic acid), 27B1 (vitamine D),

This enzyme also involvs histaminic receptor pathways.Roxatidine acetate hydrochloride receptor antagonist, has been clinically applied for the treatment of gastritis, gastric and duodenal ulcers.

CYP1A1: The human enzyme CYP1A1 is involved in the activation of major classes of tobacco procarcinogens, like PAHs and aromatic amines, and is present in many epithelial tissues. About 10% of the Caucasian population has a highly inducible form of the CYP1A1 enzyme which is associated with an increased risk for bronchial, laryngeal, and oral cavity tumors in smokers.

The CYP1A1 Ile-Val (m2) mutation in the heme-binding region results in a 2-fold increase in microsomal enzyme activity and is in complete linkage disequilibrium in Caucasians with the CYP1A1 MspI (m1) mutation, which has also been associated experimentally with increased catalytic activity Although the Ile-Val mutation in the CYP1A1 allele did not increase activity in vitro , it might be linked to other functional polymorphisms, for example in the regulatory region important for CYP1A1 inelibility. Smokers with the exon 7 Ile-Val mutation were found to have more PAH-DNA adducts in their WBCs than smokers without the variant. The amount of these adducts is also elevated in cord blood and placenta of newborns with the CYP1A1-MspI polymorphism. In lung parenchyma tissue of smokers, the concentrations of BPDE and bulky (PAH)-DNA adducts were positively correlated with CYP1A1 enzyme activity. Significant ethnic differences in the frequency of homozygous CYP1A1 MspI alleles have been observed, and both the MspI and Val alleles are rarer in Caucasian than in Japanese populations

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