Interethnic variability in cyp2d6, cyp2c9, and cyp2c19 genes. Interindividual and interethnic variabilities of drug metabolism due to the genetic polymorphism of cytochrome p450 in humans. The international congress of pharmacology was held in canada for the first time and one of the symposia was entitled interethnic differences in drug metabolism and pharmacogenetics. Thus, interethnic differences in debrisoquine hydroxylation polymorphism cyp2d6 might be partly responsible for the variations in haloperidol disposition.
In the 1970s, groups investigating the metabolism of two new drugs, sparteine and debrisoquine, both found that a significant minority of individuals were unable to metabolize these drugs 22,23. Inter ethnic variation was observed in the metabolism of losartan between cyp2c9 wild type koreans and swedes. There are many examples of differences between ethnically defined populations with regard to drug metabolizing enzymes i. The cyp2d6 gene shows marked interethnic variability, with interpopulation. Lipophilic or fatsoluble drugs are metabolized to form relatively more hydrophilic or watersoluble metabolites than the parent. It is well recognized that genetic variation in drug. Thus, interethnic differences in debrisoquine hydroxylation polymorphism cyp2d6 might be partly responsible for the variations in haloperidol disposition between races. The scientific study of interethnic differences in responses to drugs has been extant for 80 years. Interethnic variability in human drug responses request pdf. Its relevance in drug metabolism and disease susceptibility remains a central theme for pharmacogenetic research, mainly because of its genetic variability among human populations. Interethnic differences in the relevance of cyp2c9. Cyp1a2 activity has been found to be influenced by the presence of polymorphic variants which were reported to display wide interethnic variation. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems.
Human constitutive androstane receptor hcar, nr1i3 is a member of the orphan nuclear receptor family and regulates the transcription of many drugmetabolizing enzymes and drug transporters. Wide interindividual differences were observed in the metabolic ratio of losartan to e3174 metabolite even among individuals who were not carrying defective alleles cyp2c92 and cyp2c93. Human cytochrome p450 3a enzymes, particularly cyp3a4 and cyp3a5, play an important role in drug metabolism. Genetic causes of interindividual and interethnic differences. Clinical studies have confirmed oatp1b1 variants to be associated with alterations in the pharmacokinetics of substrate drugs, treatment response, and risk for drug. In silico genetic variation analysis of cytochrome. Cyp2d6 is involved in the metabolism of all of the most commonly.
Drugmetabolizing enzymes and membrane transporters work in concert to play crucial roles in drug absorption, distribution, and elimination. Interindividual and interethnic variability in drug. Pharmacogenetic variation in latin americans is understudied, which sets a barrier for the goal of global precision medicine. Interethnic variation in the metabolic inactivation of. Indices and graphical approaches for the detection of interindividual and interethnic variations in codeine metabolism q. The prevalence of unriants of enzymes such as monooxygenases, dehydrogenases, ester. Differences among patients in drug metabolism in the intestine and liver are common, are often marked. Nacetyltransferase type 2 nat2 is a phase ii drug metabolizing enzyme that plays a key role in the bioactivation of aromatic and heterocyclic amines. Interethnic differences in genetic polymorphisms of cyp2d6. More generally, xenobiotic metabolism from the greek xenos stranger and biotic related to living beings is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organisms normal biochemistry, such as any drug. Pdf interethnic variability of cyp2d6 alleles and of predicted and. Major location of drug metabolizing enzymes dysfunction can lead to impaired drug metabolismdecreased enzyme activity first pass metabolism effected may inc 24 x bioavailiability results in exaggerated pharmacological responses and adverse effects cardiac failure causes decreased blood flow to the liver. Sara abudahab, nancy hakooz, yazun jarrar, mohammad al shahhab, ahmad saleh, malek zihlif and rana dajani affiliation.
The ugt1a gene is polymorphic among ethnic groups and the aim of this study was to investigate the different ugt1a1 and ugt1a7 polymorphisms in circassians, chechens and jordanianarabs. Special attention will be paid to the variants that produce predictable changes in drug metabolism and have impacted clinical practice andor regulatory labeling. Role of cytochrome p450 2c8 in drug metabolism and. Identification and characterization of novel alternative. Interethnic diversity of nat2 polymorphisms in brazilian. Interethnic differences in drug metabolism and pharmacogenetics. Apart from drug drug interactions, some cyp2c8 genetic variants are associated with altered cyp2c8 activity and exhibit significant interethnic frequency differences. Pharmacogenetics of antiretroviral drug response and. Cancer is the second leading cause of death in the u. With the wide spectrum of drugs employed for treatment and supportive care that involve cyp2d6 in their metabolism, ethnic differences in activity of this enzyme, and the ethnically diverse population of the u. Interethnic variations in drug metabolism may be the conse quence of differences in the intestinal microflora. Cyp3a expression exhibits substantial interindividual variation, much of which may result from genetic variation.
Interindividual and interethnic variabilities of drug. Cyp3a4 and cyp3a5 genotyping by pyrosequencing bmc medical. Apr 01, 2001 the scientific study of interethnic differences in responses to drugs has been extant for 80 years. Department of biopharmaceutics and clinical pharmacy, school of pharmacy, university of jordan, amman, department of biopharmaceutics and clinical. Indices and graphical approaches for the detection of. Cyp2d6 has the largest phenotypic variation of the p450 enzymes, and some of the earliest observations of variations in drug metabolism have now been linked to polymorphisms in this gene. Genetic factors in drug metabolism american family physician.
This is due to the saturation of the enzymes needed for the metabolic pathway to take place. Open access full text article pharmacogenomics of drug. Interethnic variations of ugt1a1 and ugt1a7 polymorphisms. The pm phenotype of cyp2c19 is inherited as an autosomal recessive trait, and. I n a minority of patients taking digoxin, the drug is. Pdf genetic variation in drug transporters in ethnic. Cyp3a4 and cyp3a5 genotyping by pyrosequencing bmc. During the last 1015 years, cytochrome p450 cyp 2c8 has emerged as an important drugmetabolizing enzyme.
Cyp2c8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the. The prevalence of variants of enzymes such as monooxygenases, dehydrogenases, esterases and some transferases is not uniform, and this leads to differences in metabolism of drugs such as aspirin and diazepam. The singapore adults metabolism study we previously showed that ethnicity modi. An allelic variation in the intronic region between exon 8 and 9 of cyp2c9, ivs8109at was observed to cause a lower cyp2c9 activity in swedes but not koreans. Interethnic variability of pharmacogenetic biomarkers in mexican. Abstract interindividual and interethnic differences in response to antiretroviral drugs arvs are influenced by genetic variation. Shyong tai1,2,7 body fat partitioning does not explain the interethnic variation in insulin sensitivity among. However, it is frequently difficult to disentangle accurately the hereditary and environmental influences in phenotypic comparisons. Importantly, the corresponding genes are highly polymorphic and. In fact, the evolutionary and ethnicspecific snps on the. Pharmacogenetics and individual variation of drug response g vijay narasimha kumar asst. Clinically relevant genetic variations in drug metabolizing. Pdf interethnic variation of cyp2c19 alleles, predicted.
Interindividual variability in human drug metabolism 1st. Interethnic variation of drug metabolism there are many examples of differences between ethnically defined populations with regard to drug metabolizing enzymes i. Almost all pms in asians and africans can be attributed to cyp2c192 and cyp2c193. Cyp2c19 and cyp2d6 are important drugmetabolizing enzymes that are involved in the metabolism of around 30% of all medications. The purpose of the symposium was to discuss genetic variation of drug metabolizing enzymes in different ethnic groups. Body fat partitioning does not explain the interethnic. The international congress of pharmacology was held in canada for the first time and one of the symposia was entitled interethnic differences in drug. A total of 168 healthy jordanianarabs, 56 circassians and 54 chechens were included in this study.
The molecular aspect of interethnic and geographic. I became excited with this observation and published an article on interethnic differences of drug metabolism,14 the. In general, important genetic variation in drug effect can be envisioned at the level of drug metabolizing enzymes, drug transporters, and drug targets. Chin meng khoo,1,2 melvin kheeshing leow,2,3,4 suresh anand sadananthan,4,5 radiance lim,4,6 kavita venkataraman,5,7 eric yin hao khoo,1 s. In silico genetic variation analysis of cytochrome p450. Frequencies of clinically important cyp2c19 and cyp2d6. Interethnic variability in cyp2d6, cyp2c9, and cyp2c19. Heritable genetic variation in drug metabolizing enzyme genes has been. The ribefceiba network consortium was established to characterize interindividual and between population variations in cyp2d6, cyp2c9, and cyp2c19 drug metabolizing enzyme genotypes, which were subsequently utilized to catalog their predicted drug metabolism. We sought to determine whether differential body fat partitioning or abnormalities in muscle insulin signaling associated. Pharmacogenetics and individual variation of drug response 1. Interethnic differences in drug metabolism may be due to one of the following.
Aug 20, 20 interethnic differences in drug metabolism. In silico genetic variation analysis of cytochrome p450 2c19 and their effect in certain drugs metabolism and caucasian populations zhou et al. Cyp1a2 play an important role in the metabolism of many carcinogens and clinically important drugs. Drug metabolizing enzymes and membrane transporters work in concert to play crucial roles in drug absorption, distribution, and elimination. Cyp2c8 is highly expressed in human liver and is known to metabolize more than 100 drugs.
With the notable exceptions of cyp1a1 and cyp2e1, genes encoding cytochrome p450s, which are involved in the metabolism of 80% of all drugs used in clinical practice, are highly polymorphic. In the present study, we identified 18 hcar svs sv1sv18. The proposition of the usual dose paracelsus 14931541 the dose makes the poison 3. The cyp2d6 gene is polymorphic, with over 100 allelic variants described to. Interethnic differences in genetic polymorphisms of cyp2d6 in. This study describes pyrosequencing assays for key snps in cyp3a4 cyp3a41b, cyp3a42, and cyp3a43 and cyp3a5 cyp3a53c and cyp3a56. Interethnic variations of ugt1a1 and ugt1a7 polymorphisms in. Genetic polymorphisms have been identified for many drug metabolizing enzymes, including the cytochrome. Another affected drug metabolism by cyp2c19 therapeutic agents such as the anticonvulsant. Jun 01, 2008 the main routes of drug elimination are metabolism often in the liver and renal excretion. I n a minority of patients taking digoxin, the drug is converted to cardioinactive reduced metabolites such as dihydrodigoxin digoxin reduction products. Interethnic variation in the metabolic inactivation. Moreover, variations on drugmetabolizing enzymes and transporters not only affect drug response or toxicity but also impact the metabolism of.
Interethnic differences in the frequency of these enzyme variants seem to be the rule rather than the r. Jul 29, 2019 cyp2c19 and cyp2d6 are important drug metabolizing enzymes that are involved in the metabolism of around 30% of all medications. Explain the interethnic variation in insulin sensitivity among asian ethnicity. Interethnic variation of cyp2c19 alleles, predicted phenotypes and.
The few genomic studies conducted among africanamericans and african ethnic groups do not reflect the extensive genetic diversity within african populations. The interindividual and interethnic variations in the cyp2c9 polymorphisms are clinically significant especially in the patients on anticoagulation therapy with. Interethnic variation of drug metabolism sciencedirect. Previous studies have shown that the hcar gene produces a number of different kinds of mrna splicing variants svs in nonasian ethnicities. Interethnic variations of ugt1a1 and ugt1a7 polymorphisms in the jordanian population volume. Feb 27, 2019 drug metabolism rate there is an upper limit for the rate of drug metabolism in the vast majority of drugs. Interethnic differences in the relevance of cyp2c9 genotype.
Interethnic variability in human drug responses drug. Genetic variation in drug transporters in ethnic populations. This is unsurprising due to the vast body of literature in humans that has identified individual and group genetic variation in drug metabolism and response23 4 56. Major location of drug metabolizing enzymes dysfunction can lead to impaired drug metabolismdecreased enzyme activity first pass metabolism effected may inc 24 x bioavailiability results in exaggerated pharmacological responses and adverse effects. Genetic and environmental factors are determinants of the interindividual and interethnic variability in drug metabolism. Sendhil velan,4,8,9 yu ting ong, 4ravi kambadur,4,10 craig mcfarlane,4 peter d. There are many examples of differences between ethnically defined populations with regard to drugmetabolizing enzymes i. The impact of genetics, environmental, and geographical. In silico genetic variation analysis of cytochrome p450 2c19. Role of cytochrome p450 2c8 in drug metabolism and interactions. Department of pharmacology university of toronto, toronto, canada m5s 1a8 the survival of a population from plagues and epidemics is favored by individual variation of susceptibility to infectious disease.
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