Genetic polymorphisms in cytochrome P450 oxidoreductase influence microsomal P450-catalyzed drug metabolism (original) (raw)
Related papers
Pharmacogenomics, 2009
Aims: NADPH:CYP oxidoreductase (POR) is an essential component of several enzyme systems, including the microsomal CYP monooxygenases. We investigated genetic and nongenetic POR variability and its impact on drug-oxidation activities in human liver microsomes. Material and methods: POR mRNA, protein and activity, as well as ten major drug-oxidation activities, were measured in the microsomes of 150 Caucasian surgical liver samples. Matrix-assisted laser desorption/ionisation-time of flight mass spectrometric assays were established to determine the frequency of 46 selected POR SNPs. Multivariate log-linear regression models, including main effects and two-way interaction terms, and analyses of variance were used to identify statistically significant relationships. Results: POR phenotypes were less variable within the study population as compared with CYP phenotypes. Intronic SNPs g.18557G>A (intron 2), g.25676C>T (intron 3) and g.30986 G>A (intron 10) were associated with v...
Cytochrome P450 – Role In Drug Metabolism And Genetic Polymorphism
2018
The cytochrome P450 isoenzymes are a super family of haemoproteins that are terminal oxidases of mixed function oxidase system embedded primarily in the lipid bilayer of the endoplasmic reticulum (ER) of hepatocytes. They are so named because they are bound to membrane within a cell (cyto) and contain a haeme pigment (chrome P) that absorb light at a wavelength 450 nm when exposed to carbon monoxide. They are essential for metabolism of large number of endogenous and exogenous compounds. It has been estimated that 90% of human drug oxidation can be attributed to six main enzymes CYP 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 and CYP 3A4/5 with the two most significant enzymes being CYP 3A4 and CYP 2D6. Recently, the cytochrome isoenzymes have been shown to be important in the synthesis of steroid hormones, bile acids, arachidonic acid and in CNS function. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can c...
a r t i c l e i n f o Keywords: Biotransformation Cytochrome P450 monooxygenase NADPH:cytochrome P450 reductase Pharmacogenetics Polymorphism Xenobiotic Cytochromes P450 (CYP) are a major source of variability in drug pharmacokinetics and response. Of 57 putatively functional human CYPs only about a dozen enzymes, belonging to the CYP1, 2, and 3 families, are responsible for the biotransformation of most foreign substances including 70-80% of all drugs in clinical use. The highest expressed forms in liver are CYPs 3A4, 2C9, 2C8, 2E1, and 1A2, while 2A6, 2D6, 2B6, 2C19 and 3A5 are less abundant and CYPs 2J2, 1A1, and 1B1 are mainly expressed extrahepatically. Expression of each CYP is influenced by a unique combination of mechanisms and factors including genetic polymorphisms, induction by xenobiotics, regulation by cytokines, hormones and during disease states, as well as sex, age, and others. Multiallelic genetic polymorphisms, which strongly depend on ethnicity, play a major role for the function of CYPs 2D6, 2C19, 2C9, 2B6, 3A5 and 2A6, and lead to distinct pharmacogenetic phenotypes termed as poor, intermediate, extensive, and ultrarapid metabolizers. For these CYPs, the evidence for clinical significance regarding adverse drug reactions (ADRs), drug efficacy and dose requirement is rapidly growing. Polymorphisms in CYPs 1A1, 1A2, 2C8, 2E1, 2J2, and 3A4 are generally less predictive, but new data on CYP3A4 show that predictive variants exist and that additional variants in regulatory genes or in NADPH: cytochrome P450 oxidoreductase (POR) can have an influence. Here we review the recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s.
Pharmacogenomics of Cytochrome P450 3A4: Recent Progress Toward the “Missing Heritability” Problem
Frontiers in Genetics, 2013
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.
Pharmacogenomics, 2000
The current use and future perspectives of molecular genetic characterisation of cytochrome P450 enzymes (CYP) for drug development and drug treatment are summarised. CYP genes are highly polymorphic and the enzymes play a key role in the elimination of the majority of drugs from the human body. Frequent variants of some enzymes, CYP2A6, 2C9, 2C19 and 2D6, should be analysed in participants of clinical trials whenever these enzymes may play a role. It is suggested that a CYP genotype certificate is handed out to the volunteers or patients to avoid replicate analyses, and to allow that this information is available for future research and also for treatment with eventually needed drugs. Guidelines on what CYP alleles have to be analysed in drug development, as well as on analytical validation and CYP genotype data handling will be required. Treatment with several drugs may be improved by prior genotyping. The concepts and problems of CYP genotype-based clinical dose recommendations are presented and illustrated for selected drugs. The requirement for prospective trials on the medical and economic benefits of routine CYP genotyping is emphasised. Specific operationally defined recommendations dependent on genotype are a prerequisite for such studies and this review presents tentative CYP genotype-based dose recommendations systematically calculated from published data. Because of the multiplicity of factors involved, these doses will not be the optimal doses for each given individual, but should be more adequate than doses generally recommended for an average total population. Those CYP alleles and polymorphically metabolised drugs which are currently most interesting in drug development and drug treatment are reviewed, and more complete information is available from websites cited in this article.
A Review on INFLUENCE OF GENETIC POLYMORPHISMS OF HUMAN CYTOCHROME P450 GENE
Genetic polymorphisms in drug-metabolizing enzymes are now known to be the major determinants of inter-individual variability in drug response leading to several forms of adverse drug effects and reactions. Extensive studies has shown that identification of the genetic bases for polymorphic expression of a gene is done through intronic or exomic Single Nucleotide Polymorphisms (SNPs) which abolishes the need for different mechanism for explaining the variability in drug metabolism and fully suggests that the human Cytochrome P450 (CYP) genes are highly polymorphic. Genetic variation involved in drug metabolism may account for variations in responses to some drugs and may affect receptor adaptation, toxicity, altered drug effects and cross tolerance among various groups of individuals. Apart from the other relatively known genes such as the gluthathione and N-acetyltransferase genes which are largely involved and responsible for variances in drug metabolism and response. The Cytochrome P450 (CYP) genes has been proved to be the most common. We have discussed the clinical importance of the CYP2C9 gene alterations. This review may help researchers to understand the genetic mechanism and adverse effect of the CYP2C9 gene polymorphism.
Pharmacogenomic Role in Cytochrome P450 Enzymes-Mediated Metabolism for Drug Therapy
Journal of Urban Health Research
The rapid development of genetic science in recent decades has provided opportunities for clinical implementation. In the field of pharmacology, this opens up hope for the use of more targeted drugs with fewer side effects.Genetic variation's influence on pharmacological response has been well-established in practice. Patients' responses to pharmacological therapies can be varied, ranging from positive effects to serious adverse drug reactions (ADRs). Numerous genetic variations have been found to have a major impact on how people react to routinely prescribed medications over time, according to experts. In order to use this genetic information to inform treatment choices, a pharmacogenomic (PGx) profile can be used. PGx works on identifying and validating genomic variations that affect drug response. The generic approach to healthcare has given way to a more individualized and precise treatment paradigm as it has developed. Keywords: Adverse Drug Reactions - Genetic Variant...
Cytochrome P450 enzyme polymorphisms and adverse drug reactions
Toxicology, 2003
Adverse drug reactions (ADR) are common and many are thought to have a genetic predisposition. There has been a great deal of interest in the role of P450 enzyme gene polymorphisms in the pathogenesis of adverse reactions. The major impact to date of polymorphic P450 expression has been on pre-clinical drug development. However, the direct clinical impact of P450 polymorphisms on prediction of ADRs has been limited, largely because studies have been small and retrospective, and the literature shows an abundance of contradictory data. Furthermore, the clinical-and costeffectiveness of pre-prescription genotyping for P450 polymorphisms has not been convincingly demonstrated. Further studies that address these deficiencies are urgently needed */only then will prospective P450 genotyping become routine in clinical practice. #