References

Pharmacogenomics the inherited basis for inter-individual differences in drug response. Ann Rev Genomics Hum Genet 2001 2 9-39. 2. Ng PC, Henikoff S. Accounting for human polymorphisms predicted to affect protein function. Genome Res 2002 12 436-446. 3. Hoogendoorn B, Coleman SL, Guy CA, et al. Functional analysis of human promoter polymorphisms. Hum Mol Genet 2003 12 2249-2254. 4. Cooper DN. Human Gene Evolution. Oxford BIOS Scientific, 1999. 5. Hirschhorn JN, Lohmueller...

The PPARy Gene and Sensitivity to Thiazolidinediones

Thiazolidinediones are a novel class of antidiabetic medication that exert multiple effects beyond glycemic control and may have beneficial effects on cardiovascular risk factors. They decrease insulin resistance and reduce cardiovascular risk by improving various aspects of the cardiovascular dysmetabolic syndrome. They may reduce accelerated atherosclerosis associated with type 2 DM not only by improving glycemia and decreasing plasma insulin levels but also by increasing high-density...

Historical Perspective

Because the activity of proteins controls all cellular functions, from metabolism to cellular architecture, signal responses, motility and replication, it could be argued that all pathologies stem from the dysfunction or inappropriate expression of proteins. This accepted, it follows that there must be a set of protein metrics to describe all forms of disease, a subset of which will be diagnostic, prognostic, or useful in monitoring disease status. It is surprising, therefore, that at present...

Fluorouracil

5-Fluorouracil (5-FU) is still one of the most widely used antineoplastic agents its effect is mainly dependent on the inhibition of TS, an enzyme involved in the de novo biosynthesis of pyrimidines, by the active metabolite 2'-deoxy-5-fluorouridine monophosphate (2'-dFUMP), whereas the triphosphate metabolites interfere with nucleic acid synthesis (Fig. 7). It was evident from the time it went into use that some tumor responses to 5-FU were lower than would have been expected, although some...

Response to Vaccination

Hepatitis B vaccination continues to be the best available means of preventing and controlling hepatitis B infection. Current recombinant hepatitis B vaccines achieve seroprotection in greater than 95 of the vaccinated adult population (172). However, approximately 5 of the adults respond inadequately to the standard three doses of hepatitis B vaccine. Those adults who have an antihepatitis B (anti-HBs) titer of less than 10 mIU mL are defined as poor- and nonresponders. The lack of anti-HBs...

The Atpbinding Cassette Superfamily Of Drug Transporters

The ATP-binding cassette (ABC) superfamily includes P-glycoprotein (MDR1, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1), canalicular multiorganic anion transporter (cMOAT, ABCC2), and breast cancer resistance protein mitoxantrone resistance protein (BCRP MXR, ABCG2). These transporters play an important role in drug distribution and elimination, being expressed in the lower intestinal tract, liver, kidney, and blood-brain. The transporters also play an important role in...

Epidermal Growth Factor Receptor Family

The epidermal growth factor (EGF) pathway has been identified as a key regulator of cell growth and replication (30,31). Cumulative evidence shows that the epidermal growth factor receptor (EGFR) pathway is actively involved in a wide variety of solid tumurs, including non-small cell lung cancer (NSCLC), prostate cancer, breast cancer, stomach cancer, colon cancer, ovarian cancer, and tumors of the head and neck (30-32). Overexpression of the EGFR in cancer cells has been associated with more...

The Chlorpropamide Alcohol Flush CPAF

The CPAF is one of the earliest recognized examples of pharmacogenetics in the management of DM. Many diabetics who take the sulfonylurea, chlorpropamide, experience facial flushing after drinking even small amounts of alcohol. Sulfonylurea-induced alcohol intolerance is seen mainly, but not exclusively, with chlorpropamide and is similar to the interaction between alcohol and disulfiram. The mechanism of the reaction, however, is unclear. The main symptom is facial flushing that occurs more...

Genetic Variability In Drug Metabolizing Enzymes

Polymorphisms have now been identified in more than 20 human drug metabolizing enzymes, often with diverse frequencies in various ethnic groups (33). These include both the Phase I (which are largely P450 enzymes) and Phase II (including glucuronyl transferases, N-acetyltransferases, sulfotransferases, and glutathione transferases) enzymes. Polymorphisms in the genes encoding these enzymes usually lead to a loss of Figure 1 The interplay between genetic and environmental factors in the...

Pharmacogenetic Interactions in Hormone Replacement Therapy

Combined estrogen and progesterone therapy, whether in the form of oral contraceptive pills (OCP), in premenopausal, or hormone replacement therapy (HRT), in postmenopausal women, is associated with an increased risk for VTE. Although the absolute risk of pulmonary embolism (PE), or deep vein thrombosis (DVT), is low in healthy young women, users of OCP have a three- to sixfold increased risk of VTE compared with the nonusers (43). Traditionally, the estrogen content has been implicated as the...

Aminoglycoside Induced Deafness

Aminoglycoside antibiotic-induced ototoxicity is a major cause of irreversible deafness in many parts of the world (134,135). In China, because of the widespread use of aminoglycosides, in some areas, up to 25 of the cases of deafness were found to be caused by aminoglycosides (136). The pathogenesis of aminoglycoside-induced ototoxicity is divided into two types. One is prolonged or high-level drug exposure, and the other is idiosyncratic reaction resulting from minimal or regular exposure....

Candidate Gene Casecontrol Association Studies

Until recently, genetic polymorphisms in drug metabolism were typically described on the basis of phenotypic differences among individuals in a population. With recent advances in molecular sequencing technology, SNPs, especially in the regulatory or coding regions, are being discovered and are followed by biochemical studies assessing the phenotypic effects. Ultimately, clinical studies may allow the elucidation of polymorphisms in DME genes that have important consequences in patients. Such a...

Pharmacology and Mechanism of Action

Azathioprine (AZA) is an immunosuppressive agent that is widely used in inflammatory rheumatic diseases, including RA, where there is evidence to support its role in suppression of disease activity (57). A typical dose for RA is 1 mg kg day increasing after four to six weeks to 2-3 mg day. AZA is a prodrug, which is converted after absorption to the active agent, 6-mercaptopurine (6-MP). This is then converted by hypoxanthine-guanine phosporibosyl transferase (HGPRT) to 6-thioguanine...

Other Pharmacogenetic Markers Of Interest Drug Transporter Polymorphism

Uptake, distribution, and excretion of endogenous and exogenous compounds including antibiotics is controlled by polyspecific membrane transporters expressed in intestine, liver, kidney, placenta, testis, blood cells and the endothelial cell lining of brain capillaries, where they constitute the blood-brain barrier. Increasingly, membrane-spanning proteins involved in the inward or outward transport of a large variety of drugs have been recognized and characterized over the past years in almost...

Renin Angiotensin System Drugs ACE Inhibitors

The renin-angiotensin system (RAS) has an important role in cardiovascular health and disease, and polymorphisms of the ACE, AGT, angiotensin-II type 1 receptor (AGTR1), and CYP11B2 genes have been targeted for pharmacological research owing to the genetic variation they manifest (refer to previous section). The possibility that variation in these genes may alter drug response is therefore of considerable interest. ACE inhibitors and AT1R blockers have proved efficacious in managing CVDs, such...

Alkylating Agents

The oxazaphosphorine alkylating agents cyclophosphamide (CTX) and ifosfamide (IFX) are prodrugs that undergo extensive P450-catalyzed metabolism to yield both active (4-hydroxylated, i.e., 4-hydroxy-CTX IFX and ifo phosphoramide mustard) and thera-peutically inactive but neurotoxic N-dechloroethylated metabolites (i.e., dechloroethyl-CTX IFX and chloroacetaldehyde). Metabolism studies using cDNA-expressed CYP isoforms have shown that the production of active cytotoxic metabolites mainly depends...

Helicobacter pylori Infection and PPI

H. pylori is a major cause of gastritis, peptic ulcer disease, and gastric carcinoma. Eradication of H. pylori with a triple therapy involving a combination of antibiotics (amoxicillin, clarithromycin, metronidazole) and a proton pump inhibitor (PPI) (omeprazole, lansoprazole, rabeprazole) is effective in the treatment of these diseases. Suppression of acid secretion by PPIs increases the concentration of antibiotics and allows H. pylori to reach the growth phase and thus become more sensitive...

Coagulation Factors VII and V

The blood clotting system requires precise control of factors within and outside the coagulation cascade to prevent fatal bleeding or unwanted thrombosis. One common coding sequence polymorphism (Arg Gln353) has been found in the coagulation factor VII (F7) gene. Plasma levels of factor VII vary significantly in the general population, are associated with cardiovascular risk, and are known to be influenced by a number of different environmental factors, including sex, age, and cholesterol and...

Pharmacogenetics Of Theophylline

B2-agonists act by increasing the cAMP content of the cell control of cAMP breakdown is by tissue phosphodiesterases. Theophylline has been used in the treatment of asthma and COPD for at least 70 years. Theophylline has both bronchodilator and anti-inflammatory properties. The bronchodilator component of the drug action is thought to be at least in part mediated by phosphodiesterase inhibition in airway smooth muscle cells, leading to elevated cAMP levels and hence smooth muscle relaxation....

Pharmacogenetics of NSAIDs

There have been several studies exploring how genetic variability in pathways of relevance to NSAID metabolism and action may influence drug kinetics and or the incidence of adverse effects. Recently, Kirchheiner et al. studied genetic variability of the cytochrome P450 (CYP) 2C9 enzyme and their influence on ibuprofen metabolism. CYP2C9 polymorphisms were identified, and subjects with various combinations of the *1, *2, *3 genotypes were studied. Metabolism of the dextrorotatory S-ibuprofen...

Pharmacogenetic Targets In Cancer

For most cancers, conventional histopathologic evaluation, encompassing tumor grade and stage, is inadequate to accurately predict the biological behavior of the tumor (23 -25). Considerable effort is underway to identify and characterize the biological potential of various cancers at the molecular level. The need to predict response to therapy and determine which tumors are most likely to progress or recur or which invasive tumors will metastasize has prompted intensive efforts in search for...

Lipid Lowering Drugs Statins Fibrates

Hydroxymethylglutaryl coenzyme-A (HMGCoA) reductase inhibitors, better known as statins, are the most potent lipid-lowering agents, consistently documented to prevent or reduce cardiovascular events in primary and secondary prevention (168-170). The therapeutic potential of this type of drug is probably far greater than previously anticipated (171). Many of the nonlipid lowering effects of statins could be of major relevance to a variety of disease processes. For example, statins enhance nitric...

Glucocorticoids And Treatment Response

Glucocorticoids remain the mainstay anti-inflammatory agents used in the management of asthma and many other inflammatory lung diseases, including most forms of interstitial lung disease, and moderate and severe COPD. In all these conditions it is clear that response is variable, with some patients responding well to inhaled or oral corticosteroids, and others having little or no response. A number of groups have therefore attempted to identify genetic markers associated with treatment...

Heparin Induced Thrombocytopenia

A common adverse drug reaction is heparin-induced thrombocytopenia (HIT). The patho-genesis of HIT begins with the formation of antibodies (typically IgG), against platelet factor 4 (PF4), a protein released from platelet granules that binds to and inactivates heparin (55). IgG-heparin-PF4 complexes bind to platelet immunoglobin Fc receptors (FCy Rlla), leading to rapid uptake by splenic macrophages and thrombocytopenia. In addition, FCy Rlla-mediated platelet activation accelerates thrombin...

Decreased Detoxification of the Reactive or Toxic Metabolite

Bioinactivation of toxic metabolites can be nonenzymatic, for example, conjugation with glutathione. However, in many cases, detoxification may be catalyzed by a number of enzymes. In this respect, the glutathione-S-transferases (GST) have attracted a great deal of interest, in particular in the field of cancer, where deficient detoxification of environmentally derived carcinogens, for example, from smoking, has been implicated in the pathogenesis of cancer (82,83). However, the GST...

Acetylonium ion acetyl radical ketene Toxic

Produces hydrazine that could cause liver injury (115). Metabolism of isoniazid through this minor pathway is increased 10-fold in slow acetylators, especially when given with rifampicin (116). Two human NAT functional genes (NAT1 and NAT2) and one pseudogene (NATP) have been cloned (117). NAT2 is polymorphic in humans and has a 10-times lower Km for aromatic amines than that of NAT1. The presence of any two of the several variant alleles of the NAT2 gene leads to the slow acetylator phenotype,...

Sulfonylurea Sensitivity and MODY

MODY is a relatively rare form of familial diabetes and is part of the differential diagnosis of diabetes presenting in the first three decades of life. MODY is now known to differ fundamentally from type 2 DM in its etiology and is classified separately as type 3A. The key characteristics of this condition are an young age of onset (often before the age of 25 years), noninsulin dependence (absence of features of type 1 DM, with C-peptide positiv-ity and no requirement for insulin within five...

Renin AngiotensinAldosterone System RAAS

Interleukin And Myocardial Infarction

The Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in the development and progression of CVD by promoting sodium absorption, cardiac remodeling and norepinephrine release, and other potentially detrimental effects (Fig. 1). It also plays a significant role in controlling several elements of the extracellular matrix components manipulating this system can however reverse experimental cardiac fibrosis (11). Drugs that interfere with this system have proved to be among the most...

CYP450 System

Metabolic Arthritis

The cytochromes are a family of proteins (enzymes) that play a key role in the oxidative metabolism of drugs (e.g., -blockers, antihypertensives, antiarrhythmics, monoamine oxidase inhibitors, and so on). Approximately 70 of the human liver CYPs are accounted for by CYP1A2, CYP2A6, CYP2B6, CYP2C, CYP2D6, CYP2E1, and CYP3A (136). CYP2D6 is of particular clinical importance both because a number of commonly prescribed drugs are substrates of this enzyme and also due to interindividual and ethnic...

Association of Polymorphisms in DME and Drug Transporters with Disease Susceptibility and Progression

Biliverdin Ixa

The association of DME polymorphisms with disease susceptibility has mainly been explored in models of environmental carcinogenesis (7). In theory, genetic polymorphisms could Table 1 Application of Pharmacogenetics in Clinical Gastroenterology and Hepatology Disease susceptibility and phenotype DME polymorphism in alcoholic liver disease mEH polymorphism in HCV-related liver disease mEH and GSTM1 polymorphism in hepatocellular carcinoma MDR1 gene polymorphism in inflammatory bowel disease...

Bioethics And Its Limitations

The most influential approach to bioethics over the last 25 years has been principlism, the idea that most issues in clinical and research ethics can be resolved by reference to a set of four basic principles beneficence, respect for persons, justice, and nonmaleficence. The first three principles were set out by the U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1979) in The Belmont Report Ethical Principles and Guidelines for the...