Ethnic and genetic differences in metabolism genes and risk of toxicity and cancer ethnic and genetic differences in metabolism genes and risk of toxicity and cancer nebert, daniel w roe, amy l. The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. Drug metabolism drug metabolism is the process by which the body breaks down and converts medication into active chemical substances. Methods nicotine was administered to 92 healthy japanese subjects in the form of 1 piece of nicotine gum to investigate the potency of nicotine metabolism. Department of environmental health university of cincinnati medical center cincinnati, ohio 452670056. Since phenotype is the result of interactions between genetic makeup and the environment it is not always concordant with genotype. Dnabased nutrition testing to determine your optimal macros. A major chapter is then dedicated to clinically relevant genetic polymorphisms in human drug metabolism and resultant ethnic differences.
Paracetamol metabolism and related genetic differences. Obviously there are some unalterable facts about human metabolism and fuel partitioning, but the human race does seem to thrive on a wide variety of macronutrient intakes, provided those ratios match up with your bodys expectations. Pharmacokinetics is the study of the rate and extent of drug absorption, distribution, metabolism, and excretion. Dnabased nutrition testing to determine your optimal. The biochemistry of drug metabolism an introduction. Sex differences in human drug metabolism have also been observed with a variety of drugs.
Aug, 2017 genetics differences affect drug metabolism 1. During the last couple of years, cytochrome p450 2a6 cyp2a6. The solution to the succinylcholine mystery was among the first links drawn between genetic variation and an individuals response to drugs. Identification of genetic differences in drug metabolism. For most drugmetabolizing enzymes dmes, the functional consequences of genetic polymorphisms have been examined. Genetic polymorphisms of drug metabolizing enzymes give. It is metabolised via several metabolic pathways, including glucuronidation, sulfation, oxidation, hydroxylation, and deacetylation. Variations in drug metabolism due to genetic polymorphism. The basic principles of drug metabolism and its enzyme are discussed, with an emphases on the interindividual variations and ethnic differences of two monooxygenases cytochrome p450 cyp2d6 and. Genetic basis of drug metabolism american journal of health.
Individual variation in drug response pharmacology. Jan 15, 2014 underlying inflammation is also going to be a variable. Mar 18, 2015 drug metabolizing enzymes are commonly influenced by genetic variations. Our objective was to clarify the relationship between interindividual differences in nicotinemetabolism and cyp2a6 genetic polymorphism. Prediction of individual risk of toxicity or cancer daniel w. Ultimately, the expression of an enzyme, and therefore, the responses to drugs that it metabolizes will be an integration of all the nongenetic factors that can control the enzyme impinged upon the individuals genetic constitution. Hepatic and other organ damage may occur, especially in overdose, because of the accumulation of a toxic metabolite.
Genetic polymorphism of drug metabolizing enzymes and transporters may influence drug response. The aim is to understand the mechanism of clinically significant drug interactions, recognize potentially clinically significant genetic influences on drug efficacy and toxicity, and genetic predispositions to disease due to altered drug metabolism or transport. Differences in genetic inherited makeup among individuals affect what the body does to a drug and what the drug does to the body. Drugmetabolizing enzymes are commonly influenced by genetic variations. Cultural, environmental, and genetic influences on drug therapy.
Genetic differences in drug metabolism associated with. Cultural, environmental, and genetic influences on drug therapy and j. Genetic polymorphisms in the cytochrome p450 2a6 cyp2a6. Genetic polymorphisms have been identified for many drugmetabolizing enzymes. The genetics of alcohol metabolism role of alcohol dehydrogenase and aldehyde dehydrogenase variants howard j.
Pharmacogenomics of the population difference in drug response involves the. A study published today in the journal plos medicine has identified the five genetic variants associated with higher levels of the branchedchain. Population differences in drug response, including susceptibility to adverse drug reactions, are affected by genetic polymorphisms. Genetics of population differences in drug response. The tissue localization and subcellular distribution of drug metabolizing enzymes in the eye are described. How genetics influences medicine metabolism ausmed. This enzyme also activates a number of structurally unrelated precarcinogens including many nitrosamines and aflatoxin b1, and metabolizes certain clinically used drugs. A combination of metabolism and excretion constitutes drug elimination from the body.
Most genetic differences in drug metabolism have been found to be monogenic genetic polymorphism, meaning that they arise from the variation in one gene. It is well recognized that genetic variation in drug. Also, it is interesting to consider why striking ethnic differences in drug metabolism might exist in the first place. Ethnic and genetic differences in metabolism genes and. These processes determine the fate of a drug in the body. Pharmacogenomic studies are rapidly elucidating the inherited nature of these differences in drug disposition and effects, thereby enhancing drug discovery and providing a stronger scientific. To what extent are genetic variation and personal health linked. Inherited metabolic disorders are genetic conditions that result in metabolism problems. Clinically relevant genetic variations in drug metabolizing enzymes. This is a set of powerpoint slides with selfassessment questions interspersed throughout on drug metabolism and pharmacogenetics. The clinical role of genetic polymorphisms in drug. Genetic polymorphisms, drug metabolism and drug concentrations. Pharmacokinetic differences between ethnic groups the lancet.
The study of genetic differences in the response to drugs is called pharmacogenetics. Pharmacogenomics is a burgeoning field aimed at elucidating the genetic basis for differences in drug efficacy and toxicity, and it uses genomewide approaches to identify the network of genes that govern an individuals response to drug therapy. May, 2019 genetic polymorphism of drug metabolizing enzymes and transporters may influence drug response. Differences in drug pharmacokinetics between east asians. The concept of variable response to chemicals chemical individuality in man was first suggested by garrod in 1906 garrod, 1909. Genetic variation frequencies differ among different ethnicities, which may be associated with variation of susceptibility to adverse drug reactions among the different populations. The human flavincontaining monooxygenase form 3 fmo3 participates in the oxygenation of nucleophilic heteroatomcontaining drugs, xenobiotics, and endogenous materials. Genetic factors in drug metabolism american family physician.
Differences in metabolism between east asians and caucasians are common, especially in the activity of several phase i enzymes such as cyp2d6 and the cyp2c subfamily. Genetic polymorphism occurs when a difference in the alleles responsible for the variation is a common occurence. The fat metabolism section looks at multiple genes to help understand how your body responds to saturated fat, monounsaturated fat, and polyunsaturated fat. The study of genetic variations in drug response is called. Racial and ethnic differences in response to medicines. The pharmacogenetics of drug metabolizing enzymes is a prominent focus of this field, because genetic makeup is responsible for a significant portion of drug induced toxicity. To what extent are genetic variation and personal health. Request pdf on jun 1, 2002, d collette and others published adverse drug reactions. Genetic factors in drug metabolism request pdf researchgate. Genetic polymorphisms of drugmetabolizing en zymes give rise to distinct subgroups in the population that differ in their ability to. The main routes of drug elimination are metabolism often in the liver and renal excretion. Drug metabolism drug metabolism is the process by which the body breaks down and converts. Most people with inherited metabolic disorders have a defective gene that results in an enzyme deficiency. Understanding genetic differences in carb metabolism.
Polymorphisms of oxidation at carbon centers of drugs and their clinical significance. Currently, six forms of the fmo gene are known, but it is fmo3 that is the major form in adult human liver that is likely responsible for the majority of fmomediated metabolism. Intersubject and ethnic differences have been reported in. A number of key observations have led to the idea that response to xenobiotics might be controlled by genetics and ethnic differences.
Genetic polymorphisms in drug metabolism and disposition. Drugmetabolizing enzymes and membrane transporters work in concert to play crucial roles in drug absorption, distribution, and elimination. Genetic polymorphisms for many drugmetabolizing enzymes and. The ultimate goal of pharmacogenomics is to define the contributions of genetic differences in drug disposition and drug. Jun 01, 2008 having an understanding of the pharmacokinetic and pharmacodynamic properties of various medications is importantwhen assessing ethnic differences in drug response.
Carbohydrate metabolism gets dysfunctional when inflammation is present. Until recently, clinically important genetic polymorphisms in drug metabolism and disposition were typically discovered on the basis of phenotypic differences among individuals in the population, but the framework for discovery of pharmacogenetic traits is rapidly changing. Interindividual differences of human flavincontaining. For those with a homozygous apoa2 gene, saturated fat intake especially dairy does not send the same signal to the brain as people with the normal or heterozygous apoa2 variant that. Differences in drug pharmacokinetics between east asians and. Paracetamol acetaminophen is a worldwide used analgesic and antipyretic drug.
May 31, 2017 the fat metabolism section looks at multiple genes to help understand how your body responds to saturated fat, monounsaturated fat, and polyunsaturated fat. Since then, a small but growing number of differences in drug metabolism have been linked to genetics, helping explain why some patients benefit from a particular drug, some gain nothing, and others suffer toxic side effects. Antidepressant response varies between patients, possibly due to differences in the rate cytochrome p450 enzymes metabolise antidepressants into inactive compounds. Pharmacogenetics has elucidated the genetic basis for interindividual variability in drug response and will continue to play a key role in defining strategies to optimize drug therapy.
Genetic polymorphisms in drugmetabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of many medications. For many drugs, response and toxicity are multigenic traits and understanding relationships between a patients genetic variation in drug metabolizing enzymes. With the use of inbred strains of mice, the ah complex is shown to be an important experimental system for probing genetic differences in drug metabolism and related drug toxicities. Many genes which encode the enzymes responsible for drug metabolism show polymorphism, existing in different forms as a result of mutation. The pharmacogenetics of drugmetabolizing enzymes is a prominent focus of this field, because genetic makeup is responsible for a significant portion of druginduced toxicity. Drug metabolism is an immense area of study where drugs undergo a range of enzymemediated chemical reactions, such as oxidation, reduction, hydrolysis, hydration, conjugation, and migration.
Genetic differences in amino acid metabolism are linked to. Hereditary differences in drug metabolism find, read and cite all the research you need on researchgate. Cyp2c9, cyp2c19, and cyp2d6, which collectively account for about 40 per cent of drug metabolism mediated by cytochrome p450. Pharmacogenetic research in the past few decades has uncovered significant differences among racial and ethnic groups in the metabolism, clinical effectiveness, and sideeffect profiles of many clinically. Jan 31, 2012 sex differences in drug metabolism are recognized as a major determinant of sex differences in pharmacokinetics and an important contributor to interindividual differences in drug metabolism and, in some cases, drug action. Genetic factors can account for 20 to 95 percent of. Someone with 15 copies of the amy1 gene that exercises, sleeps well, has friends, and manages stress may respond more favorable to the same starch meal that someone with 15 copies that is sedentary. Dec 10, 2015 the effect of genetic polymorphisms differences on catalytic activity is most prominent for three isoforms. The cyp450 enzymes, cyp3a4 fentanyl and cyp2d6 codeine, hydrocodone, oxycodone, tramadol are involved in the metabolism of opioids.
Antiinflammatory agents, antituberculars, hydralazine, hypotensive agents, isoniazid, metabolism, pharmacogenetics, polymorphism, race, sulfonamides. Clinical frontiers drug metabolism 2062 am j healthsyst pharmvol 59 nov 1, 2002 tional individualized therapeutics and patient care. Genetic differences in drug metabolism are the most com mon causes for inherited variations in drug response or adverse reactions to medications. Full text full text is available as a scanned copy of the original print version. For most drug metabolizing enzymes dmes, the functional consequences of genetic polymorphisms have been examined. Drug metabolism rates are influenced by common variants in the genes encoding these enzymes. The concept of variable response to chemicals chemical individuality in. Implications of genetic variation of common drug metabolizing. Drug metabolizing enzymes and membrane transporters work in concert to play crucial roles in drug absorption, distribution, and elimination. Relationship between interindividual differences in. Previous article pharmacokinetic differences between ethnic groups next article recurrent renal stone disease sirwe agree with howard mcleods statement that ethnic origin comprises both genetic and environmental factors contributing to variability between individuals for drug metabolism, transport, and sensitivity such as receptors. Genetic influences on drug metabolism interact with other factors, such as. Pharmacogenetics is defined as the study of inherited traits that are responsible for unusual drug responses 1, 2.
In some cases, the level of an enzyme that metabolizes medications can be measured before starting the therapy. Genetic basis of drug metabolism american journal of. This spirit of investigation continued through the 20th century and is ongoing today. Genetic differences in cytochrome p450 enzymes and.
Historical aspects a number of key observations have led to the idea that response to xenobiotics might be controlled by genetics and ethnic differences. Genotype is the detailed gene structure of an individual whereas the more commonly measured phenotype is the outcome of metabolism of a drug in an individual. Nicotine was administered to 92 healthy japanese subjects in the form of 1 piece of nicotine gum to investigate the potency of nicotine metabolism. For example, in the 1950s kalow identified that some patients undergoing electroconvulsive therapy experienced a longer. The variations in these factors from individual to individual are caused by the presence of different variants of genes governing these factors which ultimately affect. Nov 01, 2002 pharmacogenetics has elucidated the genetic basis for interindividual variability in drug response and will continue to play a key role in defining strategies to optimize drug therapy.
Sex differences in drug metabolism are recognized as a major determinant of sex differences in pharmacokinetics and an important contributor to interindividual differences in drug metabolism and, in some cases, drug action. Pdf genetic variation in drug transporters in ethnic. Cultural, environmental, and genetic influences on drug. Relationship between interindividual differences in nicotine.
After a short introduction on the causes for genetic differences, the first focus is on species differences in drug and xenobiotic metabolism. The frequency varies substantially between ethnicities thus having implications on appropriate. Get a printable copy pdf file of the complete article. Genetic differences in drug metabolism associated with ocular. Variants leading to reduced or increased enzymatic activity as compared to the. It is estimated that genetic factors account for 20 to 95 per cent of patient variability in response to individual drugs. Before drug therapy, identification of either the genotype andor the phenotype for these enzymes may be of therapeutic value, particularly for drugs with a narrow therapeutic index. It is therefore suggested that genetic differences in drug metabolism be an important consideration in the clinical assessment of ocular toxicity caused by drugs and other environmental pollutants. These variations can result in differences in drug efficacy and toxicity among individuals. The pharmacogenetic differences in a number of phasei enzymes, such as cytochrome p450 cyp isoenzymes, dehydrogenases, and esterases, and phaseii conjugating enzymes have been extensively studied. Patients who have some enzyme activity are classified into four subgroups. Biochemical and genetic factors regulating dilantin metabolism in man.
1664 51 1239 654 1538 913 938 170 1042 1450 1592 1144 1444 273 1621 1493 619 467 154 778 450 606 1648 11 463 613 1039 1438 905 434 1271 946 721 385 1184 506 1271 1352 1289 935