1. Introduction
2. Genetic polymorphism of Cytochrome P450 (P450 or CYP)
The primary site of drug metabolism is the liver, where enzymes chemically change drug components into substances known as metabolites that are then bound to other substances for excretion mainly through the kidneys, lungs or bodily fluids or by intestinal re-absorption. Some drugs do not change chemical structure and are removed from the body as such. Drug pharmacokinetics and pharmacodynamics are regulated by complex chemical reactions with the participation of numerous proteins encoded by different genes, deputies for the transport and metabolism of drugs, or involved in their mechanism of action (Weinshilboum, 2003). Two different types of metabolic reactions are involved: in
2.1. P 450 genes family: From genotype to phenotype
Of all the isoforms of the P450 gene family,
2.2. CYP2D6
CYP2D6 is the most extensively studied drug metabolizing enzyme in humans and its polymorphism was the first among polymorphic P450s to be characterized at the molecular level. About 20-25% of clinically used drugs are metabolized by this enzyme including beta-blockers, antiarrhythmics, antidepressants, neuroleptics, analgesics and anti-cancer drugs. Most of them are metabolized to the inactive form; others like codeine, tramadol and tamoxifen are bio-activated. CYP2D6 is the only drug metabolizing CYP which is not inducible and therefore genetic variation plays a major role in the inter-individual variation in enzyme activity (Ingelman-Sundberg et al., 2007). The gene, located near two cytochrome P450 pseudogenes on chromosome 22q13.1, is highly polymorphic and more than 80 allelic variants related to the gene activity have been described (Zhou, 2009). The wild type allele is
2.2.1. Distribution of CYP2D6 polymorphism
Inter-ethnic differences in the distribution of
homogeneous geographic distribution could be regarded as the result of a long-term selective pressure maintaining the high frequency of alleles coding for a full-function enzyme. However, few rarely region-specific alleles associated with an altered enzymatic activity are observed and seem to be geographically dispersed over all four continents (Gaedigk et al., 2006, 2007, 2009, 2010; Luo et al., 2005). Ethnic specificity has become an integral part of pharmacogenetics research but caution is required against the use of continental labels to lump together heterogeneous populations. The Asian category, for example, is applied to individuals of distinct ethnicity and/or living in different countries or regions of the vast continent of Asia. Not surprisingly, significant variation in the distribution of pharmacogenetics polymorphism is detected among Asians (Suarez-Kurtz, 2008). Nevertheless, with increasing global migration, admixture gains relevance as an additional challenge to the successful worldwide implementation of pharmacogenetics in clinical practice. The Brazilian population, with tri-hybrid ancestral roots in Amerindian, European and African groups and five centuries of extensive inter-ethnic mating, provides a valuable model for studying the impact of admixture on the conceptual development and clinical implementation of pharmacogenetics-informed prescription. Recognition of this fact is important in the design and interpretation of pharmacogenetics clinical trials in Brazilians, but does not imply that pharmacogenetics-informed drug prescription requires investigation of individual ancestry. Rather, individual genotyping should be directed to polymorphisms of proven clinical utility, irrespective of biogeographical ancestry (Suarez-Kurtz, 2010).
2.3. CYP2C9
2.4. CYP2C19
The metabolism of tricyclic antidepressants, benzodiazepines and proton pump inhibitors is catalyzed mainly by
2.5. CYP1A2 and CYP2A6
CYP2A6 is an inducible enzyme primarily expressed in the liver and was first recognized for its involvement in the metabolism of coumarin. The
2.6. CYP2B6 and CYP2C8
2.7. CYP3A
The CYP3A drug-metabolizing enzymes facilitate the metabolism and elimination of a wide range of structurally different xenobiotics and of 50% of all clinically used therapeutic drugs. In addition, they participate in the metabolism of key endogenous substrates, such as retinoic acid, steroid hormones and bile acids (Domanski et al., 2001; Ingelman-Sundberg et al., 2007; Thummel & Wilkinson, 1998). The four
3. Personalized therapy: ethical and legal issues
Current prescribing practice involves administration of a standard “one size fits all” starting dose and is often a process of trial and error, varying the prescription until the most suitable treatment is found (Sadee, 1998). However, such a procedure exposes the patient to possible side-effects. In fact, around 21% of all outpatients suffer some kind of adverse reaction to drugs prescribed by their physician (Queneau et al., 2007). By investigating drug metabolism related to individual genetic polymorphism, pharmacogenetics has a significant impact on the clinical setting so that forensic implications may arise throughout the public health sector. The concept of “therapy with the right drug at the right dose in the right patient” was highlighted just about ten years ago (Mancinelli et al., 2000) and pharmacogenetic tests are now available for a number of drugs by biotechnology companies, some with FDA approval, as reported in Wong et al., (2010): Luminex xTag® (Luminex Corporation, TK, USA), Roche AmpliChip® (Roche, Basel, Switzerland), Affymetrix DMET® chip (Affymetrix, CA, USA), Autogenomics INFINITI™ Analyzer (Autogenomics, CA, USA), Osmetech eSensors® (WA, USA), ParagonDx (NC, USA), and ABI PRISM® SNaPshot™ (Applied Biosystems, CA, USA) and TaqMan® assays (Applied Biosystems). In addition, the Authors underlined the limitations: existing evidence to demonstrate significant and medically relevant correlations for many disease-causing genes and variants, limited detection of genetic variants within the context of each testing platform, clinical interpretation of genotype results including environmental factors, and transplanted organs interfering with testing. Nevertheless, SNP arrays covering 5 million SNPs will soon become a reality and the cost for whole-genome sequencing is rapidly decreasing (Sim & Ingelman-Sundberg, 2011). The influence of genetic polymorphism on drug failure or toxicity can be illustrated by some significant examples.
3.1. Moving to clinical practice: significant examples
An increasing number of studies on psychiatric patients have shown that genetic variation of
3.2. Legal and ethical issues
The development of pharmacogenetics has important implications in the medico-legal and forensic field because the classic topics of informed consent, shared genetic information, privacy and data base collection arise (Vaszar et al., 2002). Nevertheless the problem of orphan patients, non-responders for all available drug options, might have unforeseen consequences to avoid the label “hard to treat” (Robertson, 2001). Some patients might not want to be tested for pharmacogenetics profiles and this leads to the question of what a physician should do if a patient refuses to be genotyped. The responsibility of health care professionals will need to be defined as to who (doctors, pharmacist, clinical chemists) is responsible for the application of new technologies (genotyping) and what kind of patient counseling is needed (van Delden et al., 2004). A recent paper (Hamburg & Collins, 2010) highlighted that today about 10% of labels for FDA-approved drugs contain pharmacogenomic information — a substantial increase since the 1990s. Furthermore, there has been an explosion in the number of validated markers but relatively little independent analysis of the validity of the tests used to identify them in biologic specimens. The National Institute of Health (NIH) and the FDA will invest in advancing translational and regulatory science, and will better define regulatory pathways for coordinated approval of co-developed diagnostics and therapeutics, develop risk-based approaches for appropriate review of diagnostics to assess their validity and clinical utility more accurately, and make information on tests readily available. As the field advances, they expect to see more efficient clinical trials based on a more thorough understanding of the genetic basis of disease. The impact on the medico-legal field is evident. But, there are two schools of thought on how tort liability may affect personalized medicine, i.e., whether fear of lawsuits will tend to accelerate progress or slow it down. Tort suits include product liability suits against manufacturers and negligence suits against physicians and other providers of health-related services (Evans, 2007). Recently, Wong et al. (2010) stressed that personalized medicine by means of pharmacogenomics may have a dramatic impact on the justice system in ways we are only beginning to understand. They stated that if personalized medicine has already entered the curricula of well-regarded medical schools such as that of Johns Hopkins University (MD, USA), law schools offer no analogue. For example, “The FDA relabelled some drugs such as warfarin with CYP2C9 and vitamin K epoxide reductase complex 1 to reduce bleeding. If pharmacogenetics retrospectively reveals that the warfarin patient was at high risk and testing was not initially performed, litigation may follow. Indeed, some lawyers advertise on the Internet for cases involving warfarin-related errors. Consequently, pharmacogenomics may become part of defensive medicine”. An important issue for legal and ethical use of pharmacogenetic tests arises from the evidence of genetic polymorphism distribution in different ethnic groups.
4. Forensic investigation
In the forensic context, pharmacogenetics can assist in the interpretation of drug-related deaths, especially accidental drug poisonings or cases of sudden death with “nearly normal autopsy "(Karch, 2007), called “white autopsy” in Italy. The author claims that the ability to identify "invisible diseases" with post-mortem genetic testing has become a reality far more quickly than anyone had ever imagined and this development is not without irony: “at the same time that many clinicians are expressing frustration about the lack of tangible gains provided by the Human Genome Project and pathologists are wondering about the viability of their field, DNA technology is about to reshape the field of forensic pathology”. The role of pharmacogenetic analysis in forensic investigation has already been emphasized as the holistic approach of molecular analysis connected to macroscopic, microscopic and toxicological observations, constituting an integral part of modern medico-legal study of death (Koski et al., 2007). Nevertheless, the area of medico-legal investigation also involves occupational medicine due to the consequences on toxic-exposed workers. In this field the role of
4.1. Post mortem analysis
Genetic variation and its effects on metabolism can be applied to post-mortem analysis to help resolve cases initially believed to be suicide or classified as sudden unexplained deaths especially in cases where poisoning, incapacitation, inebriation or certain diseases where pharmacotherapy is an essential treatment (such as epilepsy, depression, cardiac diseases or diabetes) are factors in the cause of death. An additional benefit is that pharmacogenetics analysis may provide health information (certainly only via proper ethical disclosure practices) to at-risk relatives (Budowle & van Daal, 2009). As reported recently, the medico-legal community has yet to fully exploit genetic variation as a parameter in determining the causes of death as done by the National Academy of Science in recognizing the underutilization of molecular autopsies (Sajantila et al., 2010). The authors of this valuable review stressed that an individual’s pathophysiological phenotype affecting drug efficacy depends on genetic constitution and several other factors such as developmental stage, physiological and environmental factors, association with disease or specific conditions. Hence, some of these studies may be ethically unacceptable or practically impossible to perform in the clinical setting, but may be more readily performed post-mortem as part of the cause of death investigation or retrospectively with proper authorization. Therefore they recommend that serious consideration and support be given to studies of medico-legal genetics not just because of the impact on death investigation but because of the tremendous value such information can have for personalized medicine. From this point of view and due to the increasing attention paid to sudden cardiac death, the role of pharmacogenetics is now studied in more depth considering that cytochrome P450 enzymes in acquired Q-T prolongation are more prevalent than the congenital form. Several risk factors have been identified with use of Q-T prolonging drugs as the most frequent cause (van Noord et al., 2010). The CYP2D6 hydroxylation capacity has already been implicated in causing elongation of the Q-T interval: patients treated with thioridazine that inhibits CYP2D6 activity itself, may be prone to an increased risk of death due to sudden arrhythmia such as “torsades de pointes” (Lerena et al., 2002). In general, fatal drug toxicity has been associated with either slow or ultra-rapid CYP2D6 metabolism depending on the substrate activation or inactivation. Sallee et al., (2000) described the clinical course of a nine-year-old boy diagnosed with attention-deficit hyperactivity disorder, obsessive-compulsive disorder and Tourette's disorder and treated with a combination of methylphenidate, clonidine and fluoxetine. After experiencing signs and symptoms suggestive of metabolic toxicity marked by bouts of gastrointestinal distress, low-grade fever, incoordination and disorientation for more than ten months, the patient presented generalized seizures, lapsed into status epilepticus followed by cardiac arrest and subsequently expired. At autopsy, blood, brain and other tissue concentrations of fluoxetine and norfluoxetine were several-fold higher than expected based on literature reports for overdose situations. The medical examiner's report indicated death caused by fluoxetine toxicity. As the child's adoptive parents controlled medication access, they were investigated by social welfare agencies. Further genetic testing of autopsy tissue revealed a gene defect at the cytochrome P450
5. Conclusion
Current pharmacogenetics research in the clinical and medico-legal settings provides new options for disease treatment and prevention of ADR avoiding correlated death, and for screening interactions with the polymorphic P450 enzymes early on in drug development. The ensuing information will be translated into routine clinical practice in the years to come benefitting millions of patients worldwide (Ingelman-Sundberg & Sim, 2010). In the future, the research in relatively new fields such as epigenetics and small nuclear RNA mediated mechanisms will increase the number of useful biomarkers for personalized therapy. Indeed, epigenetics providing answers to interindividual variability in drug response not associated to genetic polymorphism, could represent the bridge that connects the environment to the genome (Gomez & Ingelman-Sundberg, 2009). In this respect, the area of pharmacoepigenomics has a promising future (Ingelman-Sundberg & Gomez, 2010). In medico-legal setting, molecular autopsy is becoming a reality also considering that robust techniques suitable for implementation in forensic laboratories are broadening the genetic analysis of P450 gene polymorphism. But we agree with Sajantila et al. (2010) that “in some ways this situation now confronting medico-legal geneticists is similar to the early years of the DNA level human identification era. The societal and judicial systems sought the technology and scientists had serious challenges to cope with demands. Like DNA-based identification at that time, fundamental pharmacogenetic research needs to be performed so that our knowledge is sufficient to render valid and reliable interpretations related to medico-legal genetic findings”. Significantly, Wong et al. (2010) state that personalized justice complements personalized medicine, but “personalized justice” in a firm foundation should be based on sound legal principles as well as reliable and valid evidence-based studies, not on ‘junk’ science and unsubstantiated case reports. Furthermore, the American Academy of Forensic Sciences supports the National Academy of Science’s 13 recommendations (National Academy of Sciences, 2009, as cited in Wong et al., 2010) and the following principles: the need for strong scientific foundations; laboratory accreditation; certification of technicians; the standardization of terminology; ethical protocols; governmental oversight; and the education of legal professionals, including judges, in forensic scientific methods and principles.
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