scholarly journals Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy

2005 ◽  
Vol 360 (1460) ◽  
pp. 1563-1570 ◽  
Author(s):  
Magnus Ingelman-Sundberg ◽  
Cristina Rodriguez-Antona
Keyword(s):  
Gene Expression ◽  
Cytochrome P450 ◽  
Drug Therapy ◽  
Adverse Effects ◽  
Drug Metabolism ◽  
Drug Metabolizing Enzymes ◽  
Drug Reactions ◽  
Metabolizing Enzymes ◽  
Drug Treatments ◽  
Polymorphic Enzymes

The majority of phase I- and phase II-dependent drug metabolism is carried out by polymorphic enzymes which can cause abolished, quantitatively or qualitatively decreased or enhanced drug metabolism. Several examples exist where subjects carrying certain alleles do not benefit from drug therapy due to ultrarapid metabolism caused by multiple genes or by induction of gene expression or, alternatively, suffer from adverse effects of the drug treatment due to the presence of defective alleles. It is likely that future predictive genotyping for such enzymes might benefit 15–25% of drug treatments, and thereby allow prevention of adverse drug reactions and causalities, and thus improve the health of a significant fraction of the patients. However, it will take time before this will be a reality within the clinic. We describe some important aspects in the field with emphasis on cytochrome P450 and discuss also polymorphic aspects of foetal expression of CYP3A5 and CYP3A7 .

scholarly journals Variability in human drug metabolizing cytochrome P450 CYP2C9, CYP2C19 and CYP3A5 activities caused by genetic variations in cytochrome P450 oxidoreductase

2019 ◽  
Author(s):  
Maria Natalia Rojas Velazquez ◽  
Shaheena Parween ◽  
Sameer S Udhane ◽  
Amit V Pandey
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Recombinant Proteins ◽  
Correct Diagnosis ◽  
Detailed Knowledge ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
P450 Oxidoreductase ◽  
Cytochrome P450 Oxidoreductase

AbstractA broad spectrum of human diseases are caused by mutations in the NADPH cytochrome P450 oxidoreductase (POR). Cytochrome P450 proteins perform several reactions, including the metabolism of steroids, drugs, and other xenobiotics. In 2004 the first human patients with defects in POR were reported, and over 250 variations in POR are known. Information about the effects of POR variants on drug metabolizing enzymes is limited and has not received much attention. By analyzing the POR sequences from genomics databases, we identified potentially disease-causing variations and characterized these by in vitro functional studies using recombinant proteins. Proteins were expressed in bacteria and purified for activity assays. Activities of cytochrome P450 enzymes were tested in vitro using liposomes prepared with lipids into which P450 and P450 reductase proteins were embedded. Here we are reporting the effect of POR variants on drug metabolizing enzymes CYP2C9, CYP2C19, and CYP3A5 which are responsible for the metabolism of many drugs. POR Variants A115V, T142A, A281T, P284L, A287P, and Y607C inhibited activities of all P450 proteins tested. Interestingly, the POR variant Q153R showed a reduction of 20-50% activities with CYP2C9 and CYP2C19 but had a 400% increased activity with CYP3A5. The A287P is most common POR mutation found in patients of European origin, and significantly inhibited drug metabolism activities which has important consequences for monitoring and treatment of patients. In vitro, functional assays using recombinant proteins provide a useful model for establishing the metabolic effect of genetic mutations. Our results indicate that detailed knowledge about POR variants is necessary for correct diagnosis and treatment options for persons with POR deficiency and the role of changes in drug metabolism and toxicology due to variations in POR needs to be addressed.

Biology of Heme: Drug Interactions and Adverse Drug Reactions with CYP450

2019 ◽  
Vol 18 (23) ◽  
pp. 2042-2055 ◽  
Author(s):  
Neeraj Kumar ◽  
Heerak Chugh ◽  
Damini Sood ◽  
Snigdha Singh ◽  
Aarushi Singh ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Drug Interactions ◽  
Adverse Drug Reactions ◽  
Genetic Defects ◽  
Drug Reactions ◽  
Detailed Structure ◽  
Synthesis And Degradation ◽  
Porphyrin Rings

Heme is central to functions of many biologically important enzymes (hemoproteins). It is an assembly of four porphyrin rings joined through methylene bridges with a central Fe (II). Heme is present in all cells, and its synthesis and degradation balance its amount in the cell. The deregulations of heme networks and incorporation in hemoproteins lead to pathogenic state. This article addresses the detailed structure, biosynthesis, degradation, and transportation associated afflictions to heme. The article is followed by its roles in various diseased conditions where it is produced mainly as the cause of increased hemolysis. It manifests the symptoms in diseases as it is a pro-oxidant, pro-inflammatory and pro-hemolytic agent. We have also discussed the genetic defects that tampered with the biosynthesis, degradation, and transportation of heme. In addition, a brief about the largest hemoprotein group of enzymes- Cytochrome P450 (CYP450) has been discussed with its roles in drug metabolism.

Distribution of drug-metabolizing enzymes coding genes CYP2D6, CYP3A4, CYP3A5 alleles in a group of healthy Turkish population

2018 ◽  
Vol 44 (2) ◽  
pp. 142-146
Author(s):  
İsmail Ün ◽  
İ. Ömer Barlas ◽  
Nisa Uyar ◽  
Bahar Taşdelen ◽  
Naci Tiftik
Keyword(s):  
Drug Therapy ◽  
Adverse Drug Reactions ◽  
Low Frequency ◽  
Turkish Population ◽  
Allele Frequencies ◽  
Drug Reactions ◽  
Metabolizing Enzymes ◽  
Frequency Distributions ◽  
Allelic Frequencies ◽  
Hardy Weinberg Equilibrium

Abstract Objective: Variant alleles in specific ethnic groups are important for personalized drug therapy regimens and adverse drug reactions. Therefore, the aim of this study was to investigate allelic frequencies of the CYP2D6*1, CYP3A4*5, CYP3A4*18, CYP3A5*2 and CYP3A5*4 in a group of Turkish population. Materials and methods: Three hundred and six unrelated healthy subjects who were accepted as blood donors to the Mersin University Blood Bank were included in the study after informed consent. Allelic frequencies of the CYP2D6*1 (rs3892097), CYP3A4*5 (rs55901263), CYP3A4*18 (rs28371759), CYP3A5*2 (rs28365083) and CYP3A5*4 (rs56411402) were determined by using polymerase chain reaction-restriction fragment length polymorphism assays. Results: CYP2D6 allele frequencies in detected group was 100% for CYP2D6*1 (WT/WT). CYP3A4 allele frequencies of subjects were 100% for CYP3A4*5 (C/C) and CYP3A4*18 (T/T). CYP3A5 allele were in Hardy-Weinberg equilibrium for CYP3A5*2 (p=0.142) and frequencies for C and A allele were 91% and 9% respectively. CYP3A5 allele frequencies of subjects was 100% for CYP3A5*4 (WT/WT). Conclusion: Screening of low frequency alleles by pharmacogenetic testing must not be omitted to optimize pharmacotherapy and avoid severe drug toxicities. Frequency distributions of the identified polymorphisms in the present study may contribute to the personalized drug therapy regimens and prediction of possible adverse drug reactions in the Turkish population.

scholarly journals Sequencing of the Canine Cytochrome P450 CYP2C41 Gene and Genotyping of Its Polymorphic Occurrence in 36 Dog Breeds

2021 ◽  
Vol 8 ◽  
Author(s):  
Emre Karakus ◽  
Clarissa Prinzinger ◽  
Silke Leiting ◽  
Joachim Geyer
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Gene Deletion ◽  
Homologous Sequence ◽  
Pharmacokinetic Studies ◽  
Metabolizing Enzymes ◽  
Genomic Level ◽  
Very High

Cytochrome P450 (CYP) drug metabolizing enzymes play an important role in efficient drug metabolism and elimination. Many CYPs are polymorphic and, thereby, drug metabolism can vary between individuals. In the case of canine CYP2C41, gene polymorphism was identified. However, as the first available canine genome sequences all were CYP2C41 negative, this polymorphism could not be clarified at the genomic level. The present study provides an exact characterization of the CYP2C41 gene deletion polymorphism at the genomic level and presents a PCR-based genotyping method that was used for CYP2C41 genotyping of 1,089 individual subjects from 36 different dog breeds. None of the Bearded Collie, Bernese Mountain, Boxer, Briard, French Bulldog or Irish Wolfhound subjects had the CYP2C41 gene in their genomes. In contrast, in the Chinese Char-Pei, Siberian Husky, Schapendoes and Kangal breeds, the CYP2C41 allele frequency was very high, with values of 67, 57, 43, and 34%, respectively. Interestingly, the site of gene deletion was identical for all CYP2C41 negative dogs, and all CYP2C41 positive dogs showed highly homologous sequence domains upstream and downstream from the CYP2C41 gene. CYP2C41 genotyping can now be routinely used in future pharmacokinetic studies in canines, in order to identify genetically-based poor or extensive drug metabolizers. This, together with more extensive in vitro drug screening for CYP2C41 substrates will help to determine the clinical relevance of CYP2C41, and to optimize drug treatment. Although the relative abundance of the CYP2C41 protein in the canine liver seems to not be very high, this CYP could substantially contribute to hepatic drug metabolism in dogs expressing CYP2C41 from both alleles and, when CYP2C41 shows higher catalytic activity to a given drug than other hepatic metabolic enzymes.

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