This study identifies four new potentially defective coding alleles. CYP3A5 F446S is predicted to be more catalytically defective than the splice change alone.
CYP2C9 is a clinically important enzyme, responsible for the metabolism of numerous clinically important therapeutic drugs. In the present study, we discovered 38 single nucleotide polymorphisms in CYP2C9 by resequencing of genomic DNA from 92 individuals from three different racial groups. Haplotype analysis predicted that there are at least 21 alleles of CYP2C9 in this group of individuals. Six new alleles were identified that contained coding changes: L19I (CYP2C9*7), R150H (CYP2C9*8), H251R (CYP2C9*9), E272G (CYP2C9*10), R335W(CYP2C9*11) and P489S (CYP2C9*12). When expressed in a bacterial cDNA expression system, several alleles exhibited altered catalytic activity. CYP2C9*11 appeared to be a putative poor metabolizer allele, exhibiting a three-fold increase in the Km and more than a two-fold decrease in the intrinsic clearance for tolbutamide. Examination of the crystal structure of human CYP2C9 reveals that R335 is located in the turn between the J and J' helices and forms a hydrogen-bonding ion pair with D341 from the J' helix. Abolishing this interaction in CYP2C9*11 individuals could destabilize the secondary structure and alter the substrate affinity. This new putative poor metabolizer (PM) allele was found in Africans. A second potentially PM allele CYP2C9*12 found in a racially unidentified sample also exhibited a modest decrease in the Vmax and the intrinsic clearance for tolbutamide in a recombinant system. Further clinical studies are needed to determine the effect of these new polymorphisms on the metabolism of CYP2C9 substrates.
Among the four cytochrome P450 (CYP)3A genes, CYP3A4 and CYP3A5 are the most abundantly expressed in the human liver. Eighty single nucleotide polymorphisms (SNPs) of CYP3A4/5 have been reported to the Human P450 Allele Nomenclature Committee. CYP3A4 alleles with minimal function compared with wild type include the CYP3A4*6 and CYP3A4*17. Alleles with moderately decreased or altered activity include: CYP3A4*2, *8, *11, *12, *13, *16, and *18. CYP3A5 alleles with minimal function include the splice variants CYP3A5*3, *5, *6 and CYP3A5* 10, as well as the null allele CYP3A5*7. Alleles with moderately decreased catalytic activity include CYP3A5*8 and CYP3A5*9. This report reviews the current progress in the functional characterization of CYP3A4 and CYP3A5 SNPs and provides genotyping tests for possible defective variants. A combination of genotyping tests for defective CYP3A4/CYP3A5 haplotypes will be necessary to understand the variations in the metabolism and clinical toxicity of a wide variety of clinical drugs, since these two CYP proteins have overlapping substrate specificities.
Genetic variation in CYP3A activity may influence the rate of the metabolism and elimination of CYP3A substrates in humans. We previously reported four new CYP3A4 coding variants in three different racial groups. In the present study, we examined metabolism of nifedipine by the recombinant forms of these allelic variants. Metabolism of nifedipine by the L293P (CYP3A4*18), M445T (CYP3A4*3), and P467S (CYP3A4*19) allelic variants was not significantly different from wild-type CYP3A4*1. However, F189S (CYP3A4*17) exhibited a Ͼ99% decrease in both V max and CL max of nifedipine compared with CYP3A4*1. Of 72 racially diverse individuals, CYP3A4*17 was identified in 1 of 24 Caucasian samples [1:5 Eastern European (Adygei ethnic group)]. Genotyping of an extended set of 276 genomic DNAs of Caucasians (100 from the Coriell Repository and an additional 176 from the United States) for CYP3A4*17 detected no additional individuals containing the CYP3A4*17 allele. However, additional genotyping of four more Adygei samples available from Coriell detected an additional individual carrying the CYP3A4*17 allele. New specific polymerase chain reaction-restriction fragment length polymorphism genotyping procedures were developed for the major splice variant of CYP3A5 (CYP3A5*3) and CYP3A4*17. Genotyping revealed that the two individuals carrying CYP3A4*17 were either homozygous or heterozygous for the more frequent CYP3A5*3 allele, suggesting that the two alleles may exist on the same chromosome as a new putative CYP3A poor metabolizer haplotype. We predict that individuals who are homozygous for defective alleles of both of these genes would metabolize CYP3A substrates poorly. The new genetic tests will be useful in future clinical studies to investigate genotype/phenotype associations.
More than 30 years of genetic research on the CYP2C19 gene alone has identified approximately 2,000 reference single nucleotide polymorphisms (rsSNPs) containing 28 registered alleles in the P450 Allele Nomenclature Committee and the number continues to increase. However, knowledge of CYP2C19 SNPs remains limited with respect to biological functions. Functional information on the variant is essential for justifying its clinical use. Only common variants (minor allele frequency >5%) that represent CYP2C19*2, *3, *17, and others have been mostly studied. Discovery of new genetic variants is outstripping the generation of knowledge on the biological meanings of existing variants. Alternative strategies may be needed to fill this gap. The present study summarizes up-to-date knowledge on functional CYP2C19 variants discovered in phenotyped humans studied at the molecular level in vitro. Understanding the functional meanings of CYP2C19 variants is an essential step toward shifting the current medical paradigm to highly personalized therapeutic regimens.
ABSTRACT:Our objectives were to identify CYP2D6 genetic polymorphisms in a Korean population, to compare the allele frequencies with those of other ethnic groups, and to evaluate variant-induced functional variations in dextromethorphan (DM) metabolism in vitro and in vivo. Thirty-eight single nucleotide polymorphisms of CYP2D6 were identified by direct DNA sequencing in 51 Koreans. An extended set of 707 subjects were screened for the identified variants. A group of 202 healthy subjects was subjected to phenotypic analysis on DM metabolism. CYP2D6*10 was found to be the most frequent allele (45.6%), followed by CYP2D6*1 (32.3%), *2 (9.9%), *5 (5.6%), *41 (2.2%), *49 (1.4%), and some other rare alleles (<1%). The newly identified E418K and S183Stop were assigned as CYP2D6*52 and CYP2D6*60, respectively, by the Human P450 (CYP) Allele Nomenclature Committee. Individuals having the CYP2D6*10/*49 genotype (n ؍ 5) exhibited a significant decrease in CYP2D6 metabolic activity compared with those with the CYP2D6*1/*1 genotype (n ؍ 31) (P < 0.019). Variations in CYP2D6 protein levels in liver tissues (n ؍ 49) were observed with CYP2D6 genotypes, and correlation between the CYP2D6 protein content and the activity was significant (r 2 ؍ 0.7). Given the importance of CYP2D6 in drug metabolism, subjects with the CYP2D6*10/*49 genotype may benefit from genotype analysis to achieve optimal drug therapy.Polymorphisms of the gene for cytochrome P450 2D6 (CYP2D6) influence the rate of elimination of CYP2D6 substrates, which represent approximately 20% of commonly prescribed therapeutic drugs. CYP2D6 substrates include antipsychotic drugs (haloperidol and risperidone), antiarrhythmic agents (flecainide and perphenazine), tricyclic antidepressants (imipramine and amitriptyline), -blockers (metoprolol and carvedilol), and opioids (codeine and tramadol) (Zanger et al., 2004;Ingelman-Sundberg, 2005). The CYP2D6 gene locus is highly polymorphic, and various point mutations, nucleotide deletions or insertions, gene rearrangements, and multiplication/deletion of the entire CYP2D6 gene, resulting in more than 106 different alleles
ABSTRACT:The breast cancer resistance protein (BCRP) is a member of the ATP-binding cassette transporters. The aim of the present study was to identify genetic variants of BCRP in Koreans and to assess the functional consequences of BCRP polymorphisms. Twenty single nucleotide polymorphisms (SNP), including four nonsynonymous SNP, were identified by DNA sequencing of the BCRP gene in 92 Korean subjects. BCRP V12M, Q141K, P269S, and Q126Stop were detected at frequencies of 23, 28, 0.2, and 1.9%, respectively. These four coding variants were also screened in Chinese and Vietnamese subjects; the allelic frequencies among the three populations were compared; and predictions were made as to the potential frequency of each variant.
Enzymes in the cytochrome P450 4 (CYP4) family are involved in the metabolism of fatty acids, xenobiotics, therapeutic drugs, and signaling molecules, including eicosanoids, leukotrienes, and prostanoids. As CYP4 enzymes play a role in the maintenance of fatty acids and fatty-acid-derived bioactive molecules within a normal range, they have been implicated in various biological functions, including inflammation, skin barrier, eye function, cardiovascular health, and cancer. Numerous studies have indicated that genetic variants of CYP4 genes cause inter-individual variations in metabolism and disease susceptibility. Genetic variants of CYP4A11, 4F2 genes are associated with cardiovascular diseases. Mutations of CYP4B1, CYP4Z1, and other CYP4 genes that generate 20-HETE are a potential risk for cancer. CYP4V2 gene variants are associated with ocular disease, while those of CYP4F22 are linked to skin disease and CYP4F3B is associated with the inflammatory response. The present study comprehensively collected research to provide an updated view of the molecular functionality of CYP4 genes and their associations with human diseases. Functional analysis of CYP4 genes with clinical implications is necessary to understand inter-individual variations in disease susceptibility and for the development of alternative treatment strategies.
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