INTRODUCTION:

Pharmacogenetic polymorphism is acquiring a trait with a single genetic locus with two alleles, were the slightest common allele has an incidence of about 1% or greater. Genetic polymorphism in a population is a result of more than one allele occupies a gene’s locus and can be discovered at the genotype level and/or the phenotype level based on change denzyme function.^[1]CYP superfamily encompasses drug metabolizing enzymes that can be involved in complex process such as hydrolysis, oxidation and reduction in which the functional groups of a substrate are added or deleted in phase I.

The CYP450 family encompasses18 families and 44 subfamilies be consisting up of 57 genes and 58 pseudo genes. Among them, 90 percent of drugs undergo the oxidative reactions by CYP1 which encompasses CYP subfamilies.

CYP 450 enzymes are participated in the oxidative uptake of endogenous complexes such as fatty acids, leukotrienes (LTs), steroids, prostaglandins (PGs) and in the digestion of foreign elements such as carcinogens, drugs, and environmental pollutants.^[2]Genetic polymorphisms seen in drug-metabolizing enzymes are the main basis of variability that leads to the event of adverse events and decreased therapeutic efficacy.^[3]About 50 human CYP isozymes have been recognized to date.^[4]About 20 of these genes are functionally polymorphic comprising CYP2D6, CYP2A6, CYP2C19 and CYP2C9.

Subsequently, about 40 percent of CYP-dependent drug metabolism is performed by polymorphic enzymes. Overlapping substrate specificity of enzymes, an assembly ofsingle nucleotide polymorphisms (SNPs)and distinctions among ethnic groups make likelihood of phenotypic drug response difficult.^[5,6]By adjusting drug dosage and dose of each individuals, treatment failure and unnecessary toxicity can be avoided.^[7]India, the world's succeeding greatest densely inhabited country with 1.21 billion humans, including 4,693 communities, 325 languages and 25 scripts and have extreme diversity in terms of languages, social characteristics, culture, biological, and religions in Indians and genetically they are unique from other races. Based on their national origin, Indian populations are morphologically classified into four groups Negrito, Mangoloid, Caucasoid, and Protoaustraloid. Dermatoglyphic and genomic indicator studies have proved the diversity between these two ethno geographical Indian ethnic populations.^[8]CYP enzymes located in small intestine and liver metabolize number of drugs displaying an extensive range of polymorphism of gene in Indian people due to its inter individual variation and gene mutation among them leading to significant inter-individual variances in drug clearance. Range of events including reduced therapeutic efficacy to a higher incidence of adverse events and toxicity occurs as result of metabolic differences altering the dose–response relationship.

CYP1:

CYP1A1:

CYP1A1 is mostly seen in epithelial tissues of extra hepatic organs. It catalyze polycyclic aromatic hydrocarbons creating electrophilic carcinogenic molecules and also catalyzes oxidation of several xenobiotic chemicals such as caffeine, theophylline, 7-ethoxyresoruﬁn, 7-ethoxycoumarin, chlorzoxazone, and of endogenous chemicals such as 17β-estradiol and estrone.^[9]CYP1A1 belongs to Phase I detoxification enzymes and may result in cancer in mouth and other smoking cancers. Genetic polymorphism affects both CYP1A1 regulation and structure. It is still contractory about role of CYP1A1 variants in altering genetic factor or mRNA stability.

In CYP1A1 enzymes regulation starts when the inducing agent and intracellular aryl hydrocarbon receptor (AhR) binds, were this high-afﬁnity receptor is linked with high CYP1A1 inducibility. Variety of components of the endocrine system (tumor necrosis factor α, growth factor receptor in epidermis, or glucocorticoid and estrogen receptors) can interact with AhR complex. The AhR gene shows extensive range of genetic polymorphism, and inter-individual changes in AhR phenotype.^[10]Near 10 percentage of the population have the high-affinity AhR phenotype and highly inducible CYP1A1.^[11]More than 11 alleles of cytochrome A1 have been identiﬁed, were alterations in amino occurred in CYP1A1*2B, *2C, *3, *4, *5, *6, *7, *8, *9, *11.^[12]

However, it is unclear whether these amino acid modifications alter catalytic activities in oxidation of xenobiotic, including PAHs. There could be a mark of race-related variances in the genetic polymorphism of CYP1A1, variant alleles CYP1A1*2A and CYP1A1*2C are more frequently reported in Asian (Japanese) than Caucasian populations.^[13,14]Shah et al., in their study established chance of developing lung cancer is increased to two to four times in patients with the genotype combination of CYP1A1*2A and GSTM1 (deletion polymorphisms), which advises that lung cancer susceptibility may be determined by on interactions between genes.^[15]They conﬁrmed the link between the CYP1A1*2C allele variant and GSTM1 with increased possibility of lung cancer. In north Indian people there was an eightfold rise in vulnerability to lung cancer.^[16]Some studies conﬁrmed earlier reports of CYP1A1*2C-containing genotypes altered the association between PCB exposure and risk of breast cancer.^[17]Subsequent in silicoinvestigation exposed presence of different microRNA-binding patterns in the CYP1A1 3'-UTR.^[18]

In the study conducted in South Indian subjects found that, both Ile462Val and IVS1-728G>Aare polymorphic. The haplotype analysis showed small deviation among populations. There is no strong and major linkage imbalance among these polymorphism. The 462Val variant frequency range between 8.8 to 18.9% in the current study populations, this is reliable with former reports from India.^[19,20]Aryl hydrocarbon receptor controls the CYP1A1 in humans, a transcription factor that regulates gene expression. Aryl hydrocarbon hydroxylase results formation of aryl epoxides by PAH metabolism. The action of aryl hydrocarbon hydroxylase determined by the CYP1A1 gene has been recognized in both neoplastic and normal human breast epithelium.

Some studies detected that heterocyclic amines are stimulated by CYP1A1 via N-hydroxylation process in breast tissue. CYP isoforms changes estrogens to catecholoestrogens (CEs), semiquinones and quinines by process of oxidation. These carcinogens metabolites have the capacity to form stable or depurinating DNA adducts, resulting in permanent nucleotide mutation.

CYP1A2:

CYP1A2 is mainly identified in the liver. In human liverCYP1A2 content is about 10 % to 15 % of total CYP P450 and it illustrates 40 times variations in expression levels between individuals. CYP1A2 catalyzes metabolic initiation of a variety of aryl and heterocyclic amines such as 2 amino anthracene and 2-acetylaminoﬂuorene. CYP1A2 catalyzes the activation of PAHdiols to reactive metabolites at much slower rates than CYP1A1 and 1B1.

More than 16 CYP1A2 polymorphic alleles have been identiﬁed.^[12]Alleles CYP1A2*2-*16 display amino acid alterations.^[21,22]In vitro studies revealed that the CYP1A2*11 allele variant decreases 7-ethoxyresoruﬁn O-deethylation activity.^[23]The CYP1A2*7 allele contains a splicing defect (G3534A), which causes a decrease in clozapine (an atypical antipsychotic) concentrations in vivo.^[22] CYP1A2*1F (-163C>A) is related with a high inducibility of CYP1A2 in smokers. Reports described that patients having CYP1A2*1F CC genotype treated for rheumatoid arthritis, shown a 9.7 times higher risk of overall leﬂunomide-induced toxicity than the carriers of the CYP1A2*1F A allele.^[24]It is unclear whether CYP1A2 gene polymorphism relates to cancer susceptibility in humans. Signiﬁcant relations were established among the CYP1A2*1F and the possibility of colorectal adenomas.^[25]

CYP1B1:

CYP1B1 expression is seen mainly in the endoplasmic reticulum of extrahepatic organs mainly in the steroidogenic tissues of the adrenal gland, breast, uterus, testis, ovary prostate gland. It is also expressed in various other extrahepatic tissues comprising the intestine, lung, kidney, spleen, thymus, brain, heart, and colon. Higher levels are expressed extensively in human cancers including cancers of the brain, breast, skin and testis.^[26,27]

CYP1B1 converts oestrogen to 4-hydroxylated metabolites that may result breast cancer in humans.^[28,29]CYP1B1 exhibits more than 26 polymorphism in humans; out of which 19 of these variants show amino acid changes.^[12]Hereditary glaucoma has connection with the null allele of CYP1B1.^[30]It is uncertain about the action of allelic variations linked to different forms of cancer. The combined polymorphisms in the phase II metabolic enzyme and CYP1B1 results in metabolic activation/detoxiﬁcation of oestrogen and environmental carcinogens, could be exposure reasons related with cancer risk. CYP1B1 play a significant role in the breast cancer, especially in women before the age group of 60.^[31] Meta-analysis of all available case-control studies from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database suggested link between the cytochrome CYP1B1*3 allele and breast cancer. No relation between breast cancer and CYP1B1*3 was established in Asians, mainly in Indians.

CYP2D6:

The CYP2D6 gene expressed in the CYP2D6-8 clusters on chromosome 22 in connection with the CYP2D7P and CYP2D8P pseudogenes.^[32]Gene deletion, gene conversions with associated pseudogenes and single base mutations initiating frame shift, missense, nonsense or splice-site mutations results in defective alleles.^[33,34]CYP2D6 exhibits 2% Poor metabolizers (PM), among subjects resident in Bombay, using debrisoquine in one of unique the study conducted in India.^[35]A further recent study with dextromethorphan shown 3% PM in a North Indian population.^[36]

In South India, subjects from Andhra Pradesh, Kerala, Karnataka, and Tamil Nadu have been phenotype in laboratory using dextromethorphan as probe drug.^[37] In Andhra Pradesh PM frequency is 1.8% followed by Tamil Nadu (3.6%), Karnataka (4 %) and in Kerala the 4.8%. The average frequency of PM in South India is 3.52% which is more than that described with the Chinese (0-1%) population and lower than Caucasians (5-10%).^[38]A latest study conducted with Hyderabad City population also reported a PM of 3.2%.^[39]DNA marker studies stated that Indian and European populations have a joint Caucasoid ancestor and are genetically different from those of oriental population.^[40]About 75 allelic variants presently identified in CY2D6.^[41]Variation in alleles resulted from gene mutation including gene deletion or additions point mutation, gene changes, and result in an increase, reduction, or full loss of activity.^[42,43]CYP 2D6 accounts for 2-5% of all hepatic isozymes but it metabolizes approximately 25% of all clinically used medications, including some cytotoxic, tamoxifen and many agents used to treat associated complications such as antiarrhythmic, antiemetic’s, antidepressants, antipsychotics, and analgesics. CYP2D6 (OMIM 124030), located at 22q13.1 in the CYP2D cluster is one of the best categorized genes coding for drug metabolizing enzymes (DMEs).^[44] It has a high phenotypic variations and is greatly polymorphic with more than 60 major genetic variants described to date. The CYP2D6 enzyme activity extends from complete deficiency to ultraPID metabolism. Population-specific DMEs activity patterns were observed as result of regional variances in the frequency of CYP genetic variants. In a current study, the CYP2D6 molecular variety on a total scalewhereas no similar studies on CYP2C9 and CYP2C19 were available to date.^[42]

CYP2D6 exhibits four type of metabolism, extensive metabolizers (EMs), poor metabolizers (PMs), intermediate metabolizers (IMs) and ultra-rapid metabolizers (UMs).^[45]Mainstream of population express EM being measured as the norm. There is slow metabolizing rate observed in CYP2D6 due to deficient alleles forming great number of unmetabolized drug resulting in adverse effects, drug interactions and decreased efficacy of drugs requiring CYP2D6 activation.

The UM phenotype is as result of duplication, multiplication, or amplification of active CYP2D6 genes, including predominantly the CYP2D6*2 allele, but also involving CYP2D6*1 and others.^[46,47]Individuals presenting the UM phenotype metabolize drugs at an ultrarapid rate, which cause reduction in therapeutic efficacy at standard doses.^[46,47]The CYP2D6 PM phenotype exhibits variations across different populations. The incidence of the PM phenotype have slightly increase in Indian population compared to other Asian populations of southeastern and eastern Asia, with frequencies of 1.8%–4.8%.^[48-51]The low incidence of PMs among Asians compared with whites can be due to an unequal distribution of CYP2D6 gene alleles among different populations. In Asian population, the allele CYP2D6*10 exhibits a main role in drug metabolism. This mutation has a lower substrate affinity, resulting in a shift in the drug reaction curve and, therefore, lower activity.^[52] CYP2D6*10 is seen in 50% of Asians and resulting in diminished enzyme activity in IMs.^[53,54]UM phenotype is less frequent in Indian population

CYP 3A4:

The CYP3A subfamily causes oxidative metabolism of 50% of administered drugs.^[55]CYP3A subfamily consist of four members CYP3A4, CYP3A5, CYP3A7 and CYP3A43 located in the 231-kb region of chromosome 7q21.1 have been identified in humans.^[56]Of these, in humans, CYP3A4 levels are highest in the liver and intestine, followed closely by CYP3A5. CYP 3A4 are well known for phase I metabolism.^[57]

Among them, the most important are CYP3A4 and CYP3A5. CYP3A4 metabolizes paclitaxel to its inactive hydroxylated forms. Paclitaxel is also metabolized by CYP2C8.^[58]Polymorphisms in CYP3A4 result in increased enzyme activity which may enhance metabolism of paclitaxel decreasing its therapeutic efficacy. CYP3A4 and CYP3A5 changes the balance of drug metabolism affecting the various disease metabolism.^[59]

CYP 2C9:

The most recurrently seen polymorphisms of CYP2C9 include allele *2 (c430T) in exon 3 and *3 in exon 7 resulting in impaired metabolism of warfarin and also decrease in CYP2C9 enzyme activity to approximately 12–70% and 5% of the normal level, respectively.^[60-62]A single common VKOrc1 SNP -1639G/A defines a haplotype with variant allele creating “Low dosehaplotype group (A)” and complimentary change “High dose haplotype group (b).^[63-71]CYP2C9 metabolize 90% of the S-warfarin, the more active enantiomer of Warfarin. CYP2C9 metabolizes 90% of phenytoin and 10% by CYP2C19. Polymorphisms in these genes results in adverse drug reaction (ADR) by reducing drug metabolism, increase drug concentrations.

Detection of these polymorphisms earlier could predict susceptibility to toxicity. In South Indians, the genotype allelic frequencies for CYP2C9 * 1/*1, *1/*2, *1/*3 and *2/*3 were found at ratio of 82.3%, 4.4%, 12.6% and 0.7%, respectively. A North Indian study stated a similar genotype distribution in its population.

CYP 17:

CYP17 containing 8 exons is found on chromosome 10q24.3.^[72]A single nucleotide polymorphism (SNP) has been found in the 5’ untranslated region, 27 base pair(bp) downstream from the transcription start site and 34 bp upstream from the initiation of translation. CYP 17 exhibitsa sign for prostate cancer susceptibility since it codes the cytochrome P450c17 enzyme, which facilitates two key reactions in steroid hormone biosynthesis: 17α-hydroxyprogesterone, 17α-hydroxylation of pregnenolone and progesterone and 17,20-lysis of 17αhydroxypregnenolone.^[72]

CYP2C8:

CYP 2C8 contains five different alleles (CYP 2C8*1, CYP2C8*2, CYP2C8*3, CYP2C8*4 and CYP2C8*5) and among that CYP2C8*1 is the wild-type allele exhibited in the CYP2C8 polymorphisms. The CYP2C8*3 allelic variant codes an enzyme encompassing two amino acid changes, namely R139K and K399R.^[73]The CYP2C8 enzymes play vital roles in metabolizing antidiabetic drugs apart from other anticancer and antihypertension drugs. CYP 2C8 gene shows mutations in the CYP2C8 gene at low frequencies.

The variant alleles code for enzymes with difficult activity that lead to impaired drug metabolism. CYP2C8 substrates shows low intrinsic clearance for homozygous individuals for the variant allele (*2/*2 or *3/*3) (drugs) than those who are heterozygous (*1/*2 or *1/*3).^[74] The T allele frequency was found to be 96.39% indiabetic North Indian population, which was remarkably higher than the incidence reported previously in a healthy Japanese population (0%) and an African Americans (2%) population.^[73,75]

CONCLUSION:

In conclusion, the genetic variation at CYP1, CYP2C8, CYP3A4, CYP2C9, CYP2C19 and CYP2D6 was described at global as well as in India by genotyping new population samples and by collecting data from the literature. Altered activity variants occur in all geographic regions, reaching extremely high frequencies in some populations, which has many important clinical consequences; each of the CYP genes studied shows a distinct geographic pattern of variation reflecting past evolutionary processes; effect of demography on pharmacogenetic variation should be also considered at themicro geographic scale; and several geographic regions of pharmacogenetic interest are still poorly characterized. In view of the fact that wide inter and intra-ethnic variability in allele distribution has been reported globally, genotyping needs to be done more for specific alleles in Indian populations.

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Received on 09.08.2018 Modified on 27.09.2018

Research J. Pharm. and Tech 2018; 11(12): 5681-5686.

DOI: 10.5958/0974-360X.2018.01029.6