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      Functional polymorphisms of xenobiotics metabolizing enzymes—a research topic

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      1 , 2
      Frontiers in Genetics
      Frontiers Media S.A.

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          Abstract

          The human genome harbors an impressive number of genes encoding enzymes that primarily metabolize or transport drugs or other xenobiotics (XMEs). Genetic and functional variation in these genes is tremendous and has complex consequences, depending, for example, on whether enzyme structure or expression is affected, or whether the produced metabolite is pharmacologically or toxicologically active or not. Despite numerous impressive examples of the impact of genetic variation on pharmacokinetics and drug response, today's knowledge is incomplete regarding most XME genes and fragmentary even for many well-investigated XMEs. This is one of the reasons why clinical pharmacogenetic studies are often controversial and clinical application in personalized medicine is presently limited. Advanced technology and ongoing large-scale projects are rapidly uncovering the existing genetic variation in all populations on earth, ultimately enabling the personal genome in the very near future. A wealth of mostly rare novel variants is awaiting functional characterization either by high-throughput expression/phenotyping techniques or by prediction using improved algorithms to estimate functional relevance. With this Research Topic we would like to give an up-to-date overview about the current knowledge in this field by covering both, known hard facts as well as cutting-edge advancement in novel genetic and genomic variation of XMEs and their functional consequences. Five major subtopics which include 20 research or review papers are included in this E-book. These are the following: History and current knowledge of XMEs Clinical application of CYP2C19 pharmacogenetics toward more personalized medicine (Lee, 2013, review). Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance (Zanger and Klein, 2013, review). Pharmacogenetics of human ABC transporter ABCC11: new insights into apocrine gland growth and metabolite secretion (Ishikawa et al., 2013, review). Pharmacogenomics of cytochrome P450 3A4: recent progress toward the “missing heritability” problem (Klein and Zanger, 2013, review). Clinical implications of XME gene variants ABCB1 4036A>G and 1236C>T polymorphisms affect plasma efavirenz levels in South African HIV/AIDS patients (Swart et al., 2012, research article). Genetic variations in drug-induced liver injury (DILI): resolving the puzzle (Stephens et al., 2012, opinion). MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant? (de la Torre et al., 2012, review). Molecular interactions between NAFLD and xenobiotic metabolism (Naik et al., 2013, review). Toward a clinical practice guide in pharmacogenomics testing for functional polymorphisms of drug-metabolizing enzymes. Gene/drug pairs and barriers perceived in Spain (Agúndez et al., 2012, perspective). Inter/intraethnic variability of XME gene variants Characterization of the genetic variation present in CYP3A4 in three South African populations (Drögemöller et al., 2013, research article). Frequencies of 23 functionally significant variant alleles related with metabolism of antineoplastic drugs in the Chilean population: comparison with Caucasian and Asian populations (Roco et al., 2012, research article). Pharmacogenomic diversity among Brazilians: influence of ancestry, self-reported color, and geographical origin (Suarez-Kurtz et al., 2012, review). Regulation of XME gene expression Impact of the interaction between 3′-UTR SNPs and microRNA on the expression of human xenobiotic metabolism enzyme and transporter genes (Wei et al., 2012, research article). Molecular mechanisms of genetic variation and transcriptional regulation of CYP2C19 (Helsby and Burns, 2012, review). Pharmacogenetics in cancer therapy Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia (Gervasini and Vagace, 2012, review). Multilocus genotypes of relevance for drug metabolizing enzymes and therapy with thiopurines in patients with acute lymphoblastic leukemia (Stocco et al., 2013, review). Functional polymorphisms in xenobiotic metabolizing enzymes and their impact on the therapy of breast cancer (Vianna-Jorge et al., 2013, review). High-resolution melting analysis of the common c.1905+1G>A mutation causing dihydropyrimidine dehydrogenase deficiency and lethal 5-fluorouracil toxicity (Borràs et al., 2013, research article). Polymorphisms of phase I and phase II enzymes and breast cancer risk (Justenhoven, 2012, review). Analysis of the functional polymorphism in the cytochrome P450 CYP2C8 gene rs11572080 with regard to colorectal cancer risk (Ladero et al., 2012, research article).

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          Pharmacogenomics of Cytochrome P450 3A4: Recent Progress Toward the “Missing Heritability” Problem

          CYP3A4 is the most important drug metabolizing enzyme in adult humans because of its prominent expression in liver and gut and because of its broad substrate specificity, which includes drugs from most therapeutic categories and many endogenous substances. Expression and function of CYP3A4 vary extensively both intra- and interindividually thus contributing to unpredictable drug response and toxicity. A multitude of environmental, genetic, and physiological factors are known to influence CYP3A4 expression and activity. Among the best predictable sources of variation are drug–drug interactions, which are either caused by pregnane X-receptor (PXR), constitutive androstane receptor (CAR) mediated gene induction, or by inhibition through coadministered drugs or other chemicals, including also plant and food ingredients. Among physiological and pathophysiological factors are hormonal status, age, and gender, the latter of which was shown to result in higher levels in females compared to males, as well as inflammatory processes that downregulate CYP3A4 transcription. Despite the influence of these non-genetic factors, the genetic influence on CYP3A4 activity was estimated in previous twin studies and using information on repeated drug administration to account for 66% up to 88% of the interindividual variation. Although many single nucleotide polymorphisms (SNPs) within the CYP3A locus have been identified, genetic association studies have so far failed to explain a major part of the phenotypic variability. The term “missing heritability” has been used to denominate the gap between expected and known genetic contribution, e.g., for complex diseases, and is also used here in analogy. In this review we summarize CYP3A4 pharmacogenetics/genomics from the early inheritance estimations up to the most recent genetic and clinical studies, including new findings about SNPs in CYP3A4 (*22) and other genes (P450 oxidoreductase (POR), peroxisome proliferator-activated receptor alpha (PPARA)) with possible contribution to CYP3A4 variable expression.
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            Frequencies of 23 Functionally Significant Variant Alleles Related with Metabolism of Antineoplastic Drugs in the Chilean Population: Comparison with Caucasian and Asian Populations

            Cancer is a leading cause of death worldwide. The cancer incidence rate in Chile is 133.7/100,000 inhabitants and it is the second cause of death, after cardiovascular diseases. Most of the antineoplastic drugs are metabolized to be detoxified, and some of them to be activated. Genetic polymorphisms of drug-metabolizing enzymes can induce deep changes in enzyme activity, leading to individual variability in drug efficacy and/or toxicity. The present research describes the presence of genetic polymorphisms in the Chilean population, which might be useful in public health programs for personalized treatment of cancer, and compares these frequencies with those reported for Asian and Caucasian populations, as a contribution to the evaluation of ethnic differences in the response to chemotherapy. We analyzed 23 polymorphisms in a group of 253 unrelated Chilean volunteers from the general population. The results showed that CYP2A6*2, CYP2A6*3, CYP2D6*3, CYP2C19*3, and CYP3A4*17 variant alleles are virtually absent in Chileans. CYP1A1*2A allele frequency (0.37) is similar to that of Caucasians and higher than that reported for Japanese people. Allele frequencies for CYP3A5*3(0.76) and CYP2C9*3(0.04) are similar to those observed in Japanese people. CYP1A1*2C(0.32), CYP1A2*1F(0.77), CYP3A4*1B(0.06), CYP2D6*2(0.41), and MTHFR T(0.52) allele frequencies are higher than the observed either in Caucasian or in Japanese populations. Conversely, CYP2C19*2 allelic frequency (0.12), and genotype frequencies for GSTT1 null (0.11) and GSTM1 null (0.36) are lower than those observed in both populations. Finally, allele frequencies for CYP2A6*4(0.04), CYP2C8*3(0.06), CYP2C9*2(0.06), CYP2D6*4(0.12), CYP2E1*5B(0.14), CYP2E1*6(0.19), and UGT2B7*2(0.40) are intermediate in relation to those described in Caucasian and in Japanese populations, as expected according to the ethnic origin of the Chilean population. In conclusion, our findings support the idea that ethnic variability must be considered in the pharmacogenomic assessment of cancer pharmacotherapy, especially in mixed populations and for drugs with a narrow safety range.
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              Pharmacogenomic Diversity among Brazilians: Influence of Ancestry, Self-Reported Color, and Geographical Origin

              By virtue of being the product of the genetic admixture of three ancestral roots: Europeans, Africans, and Amerindians, the present-day Brazilian population displays very high levels of genomic diversity, which have important pharmacogenetic/-genomic (PGx) implications. Recognition of this fact has prompted the creation of the Brazilian Pharmacogenomics Network (Refargen), a nationwide consortium of research groups, with the mission to provide leadership in PGx research and education in Brazil, with a population heath impact. Here, we present original data and review published results from a Refargen comprehensive study of the distribution of PGx polymorphisms in a representative cohort of the Brazilian people, comprising 1,034 healthy, unrelated adults, self-identified as white, brown, or black, according to the Color categories adopted by the Brazilian Census. Multinomial log-linear regression analysis was applied to infer the statistical association between allele, genotype, and haplotype distributions among Brazilians (response variables) and self-reported Color, geographical region, and biogeographical ancestry (explanatory variables), whereas Wright’s F ST statistics was used to assess the extent of PGx divergence among different strata of the Brazilian population. Major PGx implications of these findings are: first, extrapolation of data from relatively well-defined ethnic groups is clearly not applicable to the majority of Brazilians; second, the frequency distribution of polymorphisms in several pharmacogenes of clinical relevance (e.g., ABCB1, CYP3A5, CYP2C9, VKORC) varies continuously among Brazilians and is not captured by race/Color self-identification; third, the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of PGx studies in order to avoid spurious conclusions based on improper matching of study cohorts.
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                Author and article information

                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                08 May 2013
                2013
                : 4
                : 79
                Affiliations
                [1] 1Department of Pharmacology, University of Extremadura Cáceres, Spain
                [2] 2Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and Department of Clinical Pharmacology, University Hospital of Tübingen Tübingen, Germany
                Author notes
                *Correspondence: jagundez@ 123456unex.es

                This article was submitted to Frontiers in Pharmacogenetics and Pharmacogenomics, a specialty of Frontiers in Genetics.

                Edited by: Ulrich M. Zanger, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Germany

                Article
                10.3389/fgene.2013.00079
                3647118
                23658560
                88f1f84c-49b3-4048-89a5-fd85720e3938
                Copyright © 2013 Agúndez and Klein.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                : 18 April 2013
                : 19 April 2013
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 20, Pages: 2, Words: 1425
                Categories
                Pharmacology
                Editorial Article

                Genetics
                Genetics

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