Pharmacogenetics Is A Component Of Ecogenetics

Hereditary differences in toxicity or efficacy that result from exposure to therapeutic agents are obviously relevant to pharmacogenetics, but if the unexpected response results from exposure to other chemicals, or to physical, climatic, or atmospheric agents, it may be classified as ecogenetic. Ecogenetics encompasses genetically conditioned responses to exogenous substances from any source, and as such, includes the pharmacogenetics of drugs used in medical practice. Despite this distinction,...

The Fenphen Story Serotonergic Mechanisms Determine Drug Induced Valvular Heart Disease

Appetite suppressant medications have been used worldwide for decades for the treatment of obesity. One of the most widely prescribed anorectic agents was fenfluramine either alone or in combination with the noradrenergic drug phen-termine (''fen-phen''). When used in combination, the drugs may be just as effective as either drug alone, with the added advantage of the need for lower doses of each agent and perhaps fewer side effects. Each drug received FDA approval individually in 1996, but the...

Molecular Foundations Of Early Pharmacology And Genetics

The implications of Mendel's discoveries did not dawn on anyone until the turn of the twentieth century when their revival prompted an intense flurry of research. Lucien Cuenot in France was investigating the genetics of coat color in mice while Archibald Garrod and William Bateson in England were investigating various inborn traits in human subjects. Cuenot, Garrod, and Bateson suggested that the genetic material played an essential role in directing chemical transformations within organisms,...

Impediments To Pharmacogenetic Investigation

Human pharmacogenetic traits encompass an array of responses as broad as the effects evoked by exogenous substances in human subjects, a range that is virtually limitless. Outwardly, there is nothing to distinguish a response of hereditary origin from one that is primarily due to environmental causes. Traditionally, the classic principles of genetics applied to twin studies, family studies, and studies in larger populations are employed to differentiate them. Assignment of a casual relationship...

Pharmacokinetic Variation

Pharmacokinetics describes the time course of mechanisms that determine the level of drug (and its metabolites) in tissues and at receptor sites and terminate its biological actions (see pp. 18-50). Mathematical expressions that relate drug concentration to standard pharmacokinetic parameters (such as drug dose, dosing interval, bioavailability, rate of elimination, apparent volume of distribution, plasma half-life, and drug clearance) lend quantitative precision to estimates of the relative...

Hardy Weinberg Analysis of G6PD Deficiency

The first clear indication of the hereditary nature of drug-induced reactions associated with G6PD deficiency came after the development of a bioassay, the Table 5.10 Observed Numbers of Matings Compared with Those Expected by Application of the Hardy-Weinberg Law to Japanese Subjects3 Table 5.10 Observed Numbers of Matings Compared with Those Expected by Application of the Hardy-Weinberg Law to Japanese Subjects3

Info

Although the extent of the decrease varies somewhat between reports. For younger age groups, binding affinity appears to be substrate specific. Thus, fetal serum albumin binds salicylate with lower avidity than adult serum albumin (association constants are 1.7-2.9 x 105 M1 vs. 4.0 x 105 M1), whereas it binds bilirubin more strongly (association constants 5.2 x 107 M1 vs. 2.4 x 107 M1). For healthy elderly persons, in contrast to infants of age 1 year or younger, there is little conclusive...

Predicting Outcome and Therapeutic Benefit from Molecular Profiles of Cancer

Cancer patients with the same stage of disease can have markedly different treatment responses and overall outcomes. In addition to better systems of cancer classification and clarification of pathways that are altered in neoplastic cells, the advent of microarray technology has also prompted investigators to explore gene expression as a means of predicting the prognosis and response to chemothera-peutic decisions.116,117,119-122 Van't Veer and colleagues, for instance, have used microarray...

B6ad

Figure 9.4 Construction of double congenic mouse strains. is used to assess the effects of one genetic region on another as illustrated in Figure 9.5. Thus, differences between B6 and B6.A.D compared to those between B6 and B6.A will disclose the effect of a segment of chromosome 12 on the expression of the differential Nat allele on chromosome 8. Conversely, differences between B6 and B6.A.D compared to those between B6 and B6.D will disclose the effect of a segment on chromosome 8 on the...

Mouse Models Of The Arylhydrocarbon Receptor And Nacetyltransferase Polymorphisms

Interest in the arylhydrocarbon receptor and N-acetyltransferase polymorphisms stems from their roles in toxicity from environmental chemicals. Variant forms of the Ah-receptor protein and of N-acetyltransferase, a drug-metabolizing enzyme protein, are encoded by the responsible genes. The polymorphisms at these loci influence individual variations at pharmacodynamic and pharmacokinetic levels of drug response, respectively. The Ah locus is located on mouse chromosome 12 and the...

Influence of Recombinant DNA Technology on Pharmacogenetics

Prior to the advent of recombinant techniques, knowledge of the biochemical or pharmacological defect for a few traits had led to the discovery of the responsible genes. Certain disorders of hemoglobin and other blood-borne proteins had been attributed to the presence of missense, nonsense, or frameshift mutations that occurred within the coding region of the gene, but recombinant DNA studies revealed that genetic diversity could be created by mutation at various regulatory sites as well as...

Beginnings

We hear almost every day about the unwanted effects of prescription drugs and over-the-counter nostrums, of unsafe substances in foods, and of the perils of tobacco smoking and drinking alcohol. We cannot help but wonder why such effects occur in only a fraction of persons exposed, or why a drug that is therapeutic in one person may be ineffective, or even toxic, in another. This is the province of pharmacology. During the period in and around the 1950s, pharmacologists demonstrated, contrary...

Twin Studies

Identical (monozygous) and fraternal (dizygous) twins provide a unique resource for studying the relative importance of heredity and environment. The technique of using twin study, originally devised by Francis Galton during the nineteenth century, has been widely used for the study of human inheritance. Estimating Heritability from Twin Studies Many years of research have been devoted to theorizing about ways to assess the importance of heredity in relation to environment, but no completely...

Faulty Genomic Imprinting

From estimates made in 1995, only a small minority of genes in the mammalian genome is thought to be imprinted.98 In humans, more than 25 imprinted genes have been identified, and estimates based on mouse models indicate that as many as 100_200 may exist over the whole genome.98,99 Imprinted genes are involved in many aspects of development including fetal and placental growth, cell proliferation, and adult behavior.99 Several inherited disorders have been attributed to faulty genomic...

The Effect Of Molecular Biology On Epigenetics

During the 1960s and 1970s, observations regarding 5mC raised many more questions than could be answered with the tools that were widely available at that time. During this same period, however, the genetic code and the rules whereby cells read information encoded in DNA were established (Figure 1.1), and biologists were more inclined to think of hereditary transactions in terms of the flow of information from DNA to RNA to protein. The availability of recombinant DNA technologies for cloning,...

CYP2D6 Debrisoquine Sparteine Polymorphism

Polymorphic CYP2D6 was one of the first and most important drug-metabolizing enzyme pharmacogenetic traits to be characterized at the molecular (DNA) level. Polymorphisms of the CYP2D6 gene affect the metabolism of some 25 of frequently used drugs. CYP2D6 was originally named for the test drugs debri-soquine (an antihypertensive) and sparteine (an antiarrhythmic), but now dex-tromethorphan (an antitussive), a drug with fewer side effects, is favored to test for this polymorphism. The metabolic...

Cc2

(PEG-interferon-a-2b) Natrecor (neseritide) (darbepoietin a) OP-1 implant (osteogenic protein 1) Kineret (anakinra) Murine, IgG1 K, anti-CD20, radiolabeled (yttrium-90) Humanized, IgG1K, anti-TNF-a Recombinant B-type naturetic peptide Endothelin receptor Recombinant interleukin 1 receptor antagonist Recombinant activated protein C

The Scope Of Pharmacogenetics

The development of pharmacogenetics from 1950 to 2000 is charted in Table 2.1. Xenobiotic targets relevant to pharmacogenetics include drug-metabolizing enzymes, non-drug-metabolizing enzymes, receptors, ion channels, and other proteins, some of whose functions may be unknown or not well defined. Human sensitivities to nutritional and dietary components, occupational pollutants, or industrial chemicals, and to personal life-style habits such as smoking or drinking alcohol, may also be hallmarks...

Creating Mouse Models By Gene Targeting

In 2001, Martin Evans of the United Kingdom and Mario Capecchi and Oliver Smithies of the United States were honored for developing gene targeting,'' a technology that allows the creation of ''knockout'' and other designer strains of mice in which almost any gene can be disabled and its function probed.6,33-35 Two principal conceptual advances in the 1980s, comparable in inventiveness and impact to other revolutionary biological innovations including recombinant DNA, DNA sequencing, polymerase...

Faulty Epigenetics Germline Mutations

Germline mutations in genes that encode parts of the methylation machinery have been associated with two human diseases, the immunodeficiency centromeric instability facial anomalies (ICF) syndrome and Rett syndrome (Table 6.2). The salient features of ICF syndrome are immunodeficiency, centromere instability, and facial anomalies. This recessive disorder of childhood is associated with mutations in the DNA methyltransferase gene, DNMT3B. The mutations are largely confined to satellite DNA at...

DNA Polymorphism

Every person usually carries two copies of the genes they possess (except for sex-linked genes), but the human genome is highly polymorphic and a given person may possess an alternative DNA sequence at a particular chromosomal site that determines the usefulness of that site for genetic studies. Sites that exhibit alternative sequences are termed DNA polymorphisms, which are useful as genetic markers for the site, or for the chromosome bearing the site. From a pharma-cogenetic standpoint, such...

The Marshfield Personalized Medicine Research Project

The Marshfield Clinic's Personalized Medicine Research Project was conceived in 2000.76,83 The project was designed to coordinate existing resources of the Clinic that were unique and robust in aggregate. These resources included (1) a 12-year-old epidemiological study area encompassing 80,000 patients who had received their health care at the Clinic for several decades, (2) a highly sophisticated electronic medical record that tracked and integrated the outpatient and inpatient health care...

Testing Pharmacogenetic Hypotheses

No hard and fast rules can be quoted to guide the investigator who wishes to explore human drug responsiveness for altered pharmacogenetic mechanisms. There are, however, some general principles that are widely applicable as E. Bright Wilson explains in his book An Introduction to Scientific Research (1952). First, an experiment is almost inevitably based on a main hypothesis, and one or more auxiliary hypotheses, that the experimenter attempts to disprove the novice investigator may, in fact,...

Tpmt

Most drug-metabolizing enzymes exhibit clinically relevant genetic polymorphisms. Essentially all of the major human enzymes responsible for modification of functional groups classified as Phase I reactions (left) or conjugation with endogenous substituents classified as Phase II reactions (right) exhibit common polymorphisms at the genomic level those enzyme polymorphisms that have already been associated with changes in drug effects are separated from the corresponding...

Ugt1a1

Divided into two phenotypes rapid and slow acetylators. Slow acetylators are more susceptible to semiacute and chronic toxicity of the nervous system and chemical hepatitis from these drugs and xenobiotics. TPMT deficiency is ascribed to two major single-nucleotide polymorphisms 27 28-32 (SNPs) (at least eight have been identified) that result in low TPMT activity. TPMT deficiency is associated with life-threatening acute and delayed intolerance to immunosuppressive and antileukemic drugs...

Aldh2

Sensitivity Acetylation polymorphism Dihydropyrimidine DPYD, DPD polymorphism Glucuronosyltransferase polymorphism Multidrug resistance transporter MDR1 Phase 1 enzyme Two major SNPs Arg-144-Cys Ile-359-Leu impair metabolic efficiency Promoter variants impair or enhance vitamin K reductase efficiency SNP Glu-487-Lys Atypical SeChE Asp-70-Gly Multiple SNPs impair metabolic efficiency of NAT2 Phase 1 enzyme Splice site mutation IVS14 1G gt A Phase 2 enzyme Mutated promoter TA 7TAA polymorphism...

Ethnicity As A Starting Point For Pharmacogenetic Investigation

It follows from the preceding discussion that extrapolation across different eth-nogeographic groups for a given trait and a given drug may not be permissible. On the other hand, observations on ethnic specificity may be useful in other ways, e.g., to improve the diagnosis and clinical care of patients or to provide a fuller understanding of a given trait. For example, African, Mediterranean, and Oriental males affected by G6PD deficiency may be more susceptible to hemolysis induced by exposure...