‘Drug Reactions, Enzymes, and Biochemical Genetics‘: 50 years Later
2007; Future Medicine; Volume: 8; Issue: 11 Linguagem: Inglês
10.2217/14622416.8.11.1479
ISSN1744-8042
AutoresDavid Gurwitz, Arno G. Motulsky,
Tópico(s)Amino Acid Enzymes and Metabolism
ResumoPharmacogenomicsVol. 8, No. 11 EditorialFree Access'Drug reactions, enzymes, and biochemical genetics': 50 years laterDavid Gurwitz & Arno G MotulskyDavid Gurwitz† Author for correspondenceTel-Aviv University, Department of Human Genetics and Molecular Medicine, Faculty of Medicine, Tel-Aviv, Israel. & Arno G Motulsky† Author for correspondenceUniversity of Washington, Departments of Medicine (Medical Genetics) and Genome Sciences, Seattle, Washington, USA. Published Online:22 Nov 2007https://doi.org/10.2217/14622416.8.11.1479AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Fifty years ago, in October 1957, an article by one of us (AGM) entitled 'Drug reactions, enzymes, and biochemical genetics' was published by Journal of the American Medical Association[1]. The year 1957 saw the confluence of several scientific developments applied to medicine including the emergence of human biochemical genetics, which explained inborn errors of metabolism to be caused by enzyme malfunctions due to gene mutations. Two different adverse drug reactions (ADRs) – drug-induced hemolytic anemia due to G6PD deficiency and prolonged suxamethonium-induced apnea during anesthesia due to pseudocholinesterase deficiency – were each shown to be caused by a specific genetic enzyme variant affecting the drug's metabolism. The 1957 JAMA publication with its programmatic title suggested that "...some drug sensitivity reactions … may be produced by similar (genetic) mechanisms." In retrospect, this report delineated and conceptualized the field of pharmacogenetics, a word that was coined 2 years later by Friedrich Vogel [2], and was established as a novel discipline by Werner Kalow's 1962 monograph [3]. The field now has its own journals and international meetings, and at last count, 48 book entries at Amazon.com, over 4700 scientific articles in the PubMed database and over 1,470,000 web pages listed by Google. In a nutshell, pharmacogenetics investigates heritable factors affecting drug responses, both safety and efficacy. Pharmacogenomics, a word coined only in the mid-90's, describes a field which includes applying genomic information and technologies in drug discovery and development, as well as large-scale genomic testing for genetic variation. We use the more inclusive and focused term of pharmacogenetics here.50 years laterWhere does pharmacogenetics stand 50 years later? Are diagnostics for testing gene and/or enzyme variants that affect pharmacokinetics and pharmacodynamics commonly used for clinical decision making? Are pharmacogenetics-based diagnostic tests covered financially by public sources or insurance as are other medical tests? Most importantly: are old and new medicines safer and more effective as a result of applying pharmacogenetics knowledge in drug development and in clinical practice? Sadly, the reply to these questions is negative, with very few exceptions. While many more effective drugs exist now than in 1957, medicines are not much safer today, they often cost a lot more while still being prescribed for most conditions along the old 'one drug fits all' concept. Determination of dosage according to patient-specific phenotypic or genotypic laboratory tests is rare. With few exceptions, such as monoclonal antibody treatment in oncology, clinicians are not using pharmacogenetic testing as part of drug selection, and are often not knowledgeable about the few available tests. The widely publicized VioxxTM recall, although not proven to be related to genetic susceptibility, highlighted the drug safety issue, and increased public awareness to morbidity and mortality caused by medicines. A recent comprehensive report by the CDC based on a 2-year long US national survey stated that ADRs were directly implicated in 6.7% of all emergency department visits leading to hospitalization, with even higher figures for women and for the most vulnerable population segments – the very young and very old [4]. Similarly high percentages of ADRs as a direct cause of hospital admissions were reported in the UK [5], where a national health service is in place. The exact proportion of genetically caused ADRs (including drug nonresponsiveness) among all ADRs cannot yet be defined, but evolving data suggest an increasing role of genetic variation [6,7]. However, a majority of ADRs are likely the result of drug–drug interactions or some drugs causing specific organ damage of unknown origin, such as liver or kidney toxicity. It should not be expected that pharmacogenetics would explain all ADRs. However, there are documented withdrawals from the market of drugs whose primary metabolizing enzymes are associated with significant genetic variation [7], although none of these variants has been shown to be directly responsible for withdrawal of the corresponding drug. For example, the obesity drug dexfenfluramine and the diabetes drug troglitazone (both withdrawn in 1997) are primarily metabolized by the highly polymorphic liver enzymes CYP2D6 and CYP2C19, respectively. Nevertheless, concerns have been raised that pharmacogenetic information alone would not suffice for rescuing the majority of discontinued medicines [8].In this context it is noteworthy that the year 2007 also marks the 30th anniversary for the discovery of CYP2D6 (originally called debrisoquine hydroxylase) [9], a key drug-metabolizing enzyme implicated in the metabolism of about a quarter of current medicines, including the majority of antipsychotics and antidepressant drugs [7]. Indeed, 30 years later, CYP2D6 remains one of the most researched human genes, and is already mentioned in over 3300 scientific articles in the PubMed database. However, despite the fact that a US FDA-approved test for identifying CYP2D6 'poor metabolizers' is on the market since 2005 [10], the clinical uptake of this test has been very slow.Following the successful completion of the human genome sequencing project [11,12], rapid applications of the new insights to medicine including personalized pharmacotherapy were expected and widely publicized. However, most pharmaceutical companies were reluctant to get involved, fearing that personalized therapy would destroy the profitable 'one drug fits all' concept by restricting markets for a given drug. Five years ago, Motulsky noted that "the field is likely to have an impact on choice of drug therapy and avoidance of adverse events, but is unlikely to lead to a revolution in therapeutics" [13]. This sobering observation remains true to this day, and is likely to remain so for some time, even when genome-wide association studies (GWAS) investigate cohorts of many thousands of individuals with complex common diseases for presence of disease risk alleles [14]. Some genes have been identified with this approach for several complex common diseases [14,15], but the small quantitative contribution of such a gene (or DNA region) to the complex disease phenotype will usually make this gene unsuitable for diagnostic testing to suggest specific therapy at this time.Single or multiple genes in pharmacogeneticsThe 50 year anniversary for the October 1957 article by AGM is an opportunity to re-examine the reasons for the slow clinical uptake of pharmacogenetics in a manner that assures maximal future benefits for prevention and medical care. Even though a single gene abnormality has explained most ADRs so far (Table 1 & 2), it is becoming apparent that both ADRs and variable drug responses may often be caused by the combined action of multiple genes. The widely used anticoagulant warfarin is frequently associated with hemorrhage and leads the list of medicines associated with serious ADR in both the USA [4] and the UK [5]. Recent studies show that use of warfarin may be made safer and more effective by considering patients' genotype for CYP2C9, as well as for vitamin K epoxide reductase (VKORC1) [16]. Since these two genes only account for approximately one half of the variation in warfarin's anticoagulant effects [16], other yet undetected genes in addition to environmental factors are likely to be involved in warfarin metabolism. Detailed research and extensive clinical studies including evaluation of clotting status and genotyping will, therefore, be required before routinely including genotyping to institute and monitor warfarin therapy.Other examples are likely to follow since gene variants acting on different pathways of drug metabolism, drug receptors and drug transporters and on different routes of excretion may interact to achieve variable end results of drug action. Thus, the mechanisms of genetically influenced drug effects may often be polygenic, as already suggested some years ago when a striking similarity of identical twins as compared with fraternal twins was discovered when studying metabolism of a variety of drugs [17].Environment & heredityIt is becoming apparent that gene products interact with, and their expression and function is affected by, a variety of environmental factors such as nutrition, alcohol, smoking, environmental xenobiotics, pathogens, chronic disease, other medications and stressful life events. Indeed, the intricate gene–environment interplay reflected by individual differences in all aspects of health and disease also extends to drug response. Thus, one should not expect to personalize pharmacotherapy entirely with genetic information alone, even with complete individual genomes at hand [6,7,13,18]. In other words, pharmacogenetic testing will not be capable of eliminating ADRs, as many of them are the result of environmental, rather than heritable factors. As an example, alcohol consumption and smoking are both implicated in the expression of the metabolic enzyme CYP2E1, thereby affecting the pharmacokinetics of certain drugs [19].However, emerging knowledge of genotype/phenotype correlations of drug response will begin to guide clinicians in choosing optimal treatment options. This is most obvious for choices concerned with reducing ADR risks and maximizing drug efficacy when choosing between various therapies, in particular when a drug has a narrow therapeutic index. Applying pharmacogenetic knowledge to patient care may help to promote the clinical uptake of the relevant diagnostic tests, as consumers will want them and policy makers are more inclined to cover the costs when the potential of reducing overall healthcare burden [6] has been demonstrated.Existing medicines should be emphasizedUsing CYP2C9 and VKORC1 genotyping for improving the safety of warfarin illustrates that the safety of a widely-employed 'old fashioned' medicine may be improved with new pharmacogenetics knowledge [16]. Another example is the estrogen antagonist tamoxifen which reduces the risk of breast cancer recurrence and is usually prescribed for 5 years following primary treatment for estrogen receptor-positive breast cancer. However, new studies have demonstrated that tamoxifen is merely a prodrug for the more potent estrogen receptor antagonist endoxifen, formed in vivo by the liver enzyme CYP2D6. Accordingly, patients who are deficient for CYP2D6 activity (5–8% of European origin) have much lesser benefit and are at greater risk for cancer relapse [20]. Luckily alternatives are available for these patients such as aromatase inhibitor drugs that provide similar protection by lowering the endogenous production of estrogen. In this example a simple pharmacogenetics diagnostic test assumes major therapeutic significance.Some third world applicationsAmodiaquine is a drug with a narrow therapeutic index that is metabolized primarily by CYP2C8 and is widely used in Africa as an antimalarial agent. Approximately 4% of the Zanzibar population are 'slow CYP2C8 metabolizers' and are at much higher ADR risk [21]. Of note, the same CYP enzyme (along with CYP2C9) is also implicated in clearance of the antimycobacterial drug dapsone [22], commonly used for both the treatment of leprosy and Pneumocystis carinii pneumonia, highlighting the importance of screening for genetic enzyme deficiencies in the developing world with its high frequency of malaria, pneumonia associated with AIDS and leprosy. Thus, pharmacogenetics should not be viewed as 'luxury medicine', and may become relevant in countries where healthcare budgets are small.Population differences in allele distributions for many genes, including those relevant for pharmacogenetic testing, are now well documented. Fifty years ago, Motulsky noted that "since a given gene may be more frequent in certain ethnic groups, any drug reaction that is more frequently observed in a given racial group, when other environmental variables are equal, will usually have a genetic basis", which remains valid today. Pharmacogenetics-based diagnostics would require gathering knowledge on relevant allele distributions for local populations. Often, phenotypic tests, such as determination of thiopurine methyltransferase (TPMT) activity prior to treatment with azathioprine to prevent transplant rejection or 6-mercaptopurine toxicity in acute leukemia therapy [23] are superior to DNA genotyping. Phenotypic tests for TPMT may be more predictive for drug response given the wide enzyme levels variation in heterozygotes whose enzyme levels, therefore, cannot be predicted from genotyping alone. Similar considerations apply to preference for phenotypic enzyme testing as compared with DNA tests for heterozygote testing of other pharmacogenetic enzyme defects with heterozygotic variability.Incentives are neededA key obstacle to incorporation of diagnostics for pharmacogenetics into routine clinical practice is that most medicines in current use – including those portrayed in the above examples and Table 1 – are generics, and the private sector is reluctant about investing in development of relatively unprofitable diagnostic and therapeutic agents. A key driver for the clinical uptake of pharmacogenetics must therefore include generous incentives for developing pharmacogenetics-based diagnostics for existing medicines. Such incentives may include earmarked public funding including costs for test-associated clinical trials, as well as modified regulations for their facilitated marketing approval [24]. Potentially, such regulations for pharmacogenetics-based diagnostics might be similar to the Orphan Drug Act of 1983 (USA) – which grants a 7-year exclusivity and tax refunds for drugs aimed at treating conditions affecting less than 200,000 US citizens. Indeed, for the life-threatening ADRs, the numbers seem to fall within this range. Notably, a 2006 European Commission report on pharmacogenetics concluded that a key barrier for the clinical uptake of pharmacogenetics was "lack of incentives for developing diagnostics to improve the safety and efficacy of current drugs by re-licensing along with a pharmacogenetics diagnostic" [25]. While the FDA has become active towards the use of pharmacogenetics information in the drug approval process [7,26], support for approving new diagnostics concerned with existing medicines would be highly desirable. The NIH can play an important role by reshaping research priorities towards assuring improved vigilance for existing drugs rather than putting most of its research efforts on new drug targets [27].Incentives are also needed for research into the pharmacoeconomics aspects of pharmacogenetic testing, as only few studies have adequately addressed their healthcare economics implications [6,28]. Here again research funding would have to come primarily from the public sector, as most drugs fitting for inclusion in such studies are generics, and there are insufficient drivers for the pharmaceutical industry to invest in the economic evaluation of pharmacogenetic testing for such medicines [25].The futureThe contrast between the slow evolution of pharmacogenetics over the last 50 years is striking when compared with the amazing advance of the space program, an example of technological progress which also started in October 1957 with the launch of Sputnik 1. Unfortunately, immediate clinical applications of pharmacogenetics are not feasible in most instances since extensive clinical investigations in pharmacogenetics to prove clinical utility will need to be done. When initiating such studies, an emphasis on safety and effectiveness of existing drugs should be a priority. Considering the societal burden of ADR-related morbidity, the escalating healthcare costs for aging societies in developed countries and the need for better treatment of the persisting disease endemics in the developing world, the potential for improved health globally is significant. Hopefully, the practical applications of pharmacogenetics to clinical medicine and public health will be realized in a not too distant future.Table 1. Selected drugs, related genes, altered clinical effects and testing methods with available pharmacogenetics diagnostics.Drug(s)Gene(s)Altered clinical effects(s)Testing method(s)AbacavirHLA variantsImmunologic reactionsDNA, immunologicAmodiaquineCYP2C8PM need lower dose for preventing malariaDNAAzathioprine; 6-mercaptopurineTPMTBone marrow aplasiaEnzyme assay, DNACodeineCYP2D6Required for drug activation – reduced pain reliefDNA5-fluorouracilDPDPM need lower doseEnzyme assay, DNAIrinotecanUGT1A1Decrease expression in PM – neutropeniasEnzyme assay, DNAIsoniazidNAT2Peripheral neuropathyEnzyme assay, DNA, acetylation phenotypeMetforminOCT2Some alleles associated with toxicityDNAMethadoneCYP2B6PM need lower maintenance doseDNAOxidizing drugsG6PDHemolytic anemiaEnzyme assayQT prolonging antiarrhythmicsIon channel genesArrhythmia, torsade de pointesDNAStatinsHMG-CoA reductaseAltered response for lipid reductionDNASuxamethoniumBuChEProlonged apnea during anesthesiaEnzyme assay with dibucaine or DNATamoxifenCYP2D6PM at higher risk for cancer recurrenceDNAWarfarinCYP2C9VKORC1Hemorrhage, variable dosage requirementsDNANote that all pharmacogenetic traits listed (with the exception of warfarin) are inherited by monogenic inheritance. The list is compiled from [29,30] and from the Pharmacogenetics and Pharmacogenomics Knowledge Base [31]; for further examples see [101].BuChE: Butyrylcholine esterase; CYP: Cytochrome P450; DPD: Dihydropyrimidine dehydrogenase; G6PD: Glucose-6-phosphate dehydrogenase; HLA: Human leukocyte antigen; HMG-CoA reductase: 3-hydroxy-3-methyl-glutaryl-CoA reductase; NAT2: N-acetyltransferase 2; OCT2: Organic cation transporter 2; PM: Poor metabolizers (individuals with two inactive alleles); TPMT: Thiopurine methyltransferase; UGT1A1: UDP-glucuronyltransferase 1A1; VKORC1: Vitamin K epoxide reductase complex 1.Table 2. Cancer-related (somatic) pharmacogenetics*.Drug(s)GeneAltered clinical effect(s)Testing method(s)CetuximabEGFR (HER1)Btter response with increased copies of geneDNA5-fluorouracilTSPoor response with increased copies of geneDNAImatinibPhiladelphia chromosomeClinical response in most of CML patientsCytogenetics, DNATrastuzumabHER2No drug effect in HER2 negative patientsDNA*Denotes genes for which somatic mutations in tumor tissues may affect drug response. Genotyping or phenotyping requires tumor biopsy tissues.The list is compiled from [29-30] and from the Pharmacogenetics and Pharmacogenomics Knowledge Base [31]; for further examples see [101].CML: Chronic myeloid leukaemia; EGFR: Epidermal growth factor receptor; HER2: HER2/neu (also known as ErbB-2); TS: Thymidylate synthetase.Financial & competing interests disclosureAGM owns stock in Johnson & Johnson; Pfizer (pharmaceutical companies); Amgen (biotech company). AGM's work is partly supported by NIEHS Center Grant P30ES07033. 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AGM's work is partly supported by NIEHS Center Grant P30ES07033. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download
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