Antibodies as a Probe in Cytochrome P450 Research

  title={Antibodies as a Probe in Cytochrome P450 Research},
  author={M. Shou and A. Y. Lu},
  journal={Drug Metabolism and Disposition},
  pages={925 - 931}
  • M. Shou, A. Y. Lu
  • Published 2009
  • Biology, Medicine
  • Drug Metabolism and Disposition
Cytochrome P450 (P450) is the superfamily of enzymes responsible for biotransformation of endobiotics and xenobiotics. However, their large isoform multiplicity, inducibility, diverse structure, widespread distribution, polymorphic expression, and broad overlapping substrate specificity make it difficult to measure the precise role of each individual P450 to the metabolism of drugs (or carcinogens) and hamper the understanding of the relationship between the genetic/environmental factors that… Expand
Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity
The majority of marketed small-molecule drugs undergo metabolism by hepatic Cytochrome P450 (CYP) enzymes (Rendic 2002). Since these enzymes metabolize a structurally diverse number of drugs,Expand
In vitro techniques to study drug-drug interactions of drug metabolism: Cytochrome P450
Approaches are discussed for the generation and use of in vitro data on metabolic reversible inhibition, time-dependent inhibition and induction to make predictions of in vivo drug–drug interactions.Expand
Improvement of the chemical inhibition phenotyping assay by cross-reactivity correction
Correcting in vitro chemical inhibition results for cross-reactivities appear to offer a straightforward and easily adoptable approach to provide improved fmCYP data for a drug. Expand
Inhibition of cytochrome P450 enzymes involved in ketamine metabolism by use of liver microsomes and specific cytochrome P450 enzymes from horses, dogs, and humans.
Ketamine N-demethylation was stereoselective in single human CYP3A4 and canine CYP2C21 enzymes and to address drug-drug interactions in these animal species, investigations with single CYPs are needed. Expand
Translational Drug Discovery Research: Integration of Medicinal Chemistry, Computational Modeling, Pharmacology, ADME, and Toxicology
Translational drug discovery research is focused on selective utilization of CADD; absorption, distribution, metabolism, and excretion; toxicology; PK; and PD evaluations, which identify potential liabilities early so as to minimize late-stage failures during drug development. Expand
Identification of proteins associated with pyrethroid resistance by iTRAQ-based quantitative proteomic analysis in Culex pipiens pallens
This is the first study to use modern proteomic tools for identifying pyrethroid resistance-related proteins in Cx. Expand
The Expression and Prognostic Significance of Retinoic Acid Metabolising Enzymes in Colorectal Cancer
It is shown that the retinoic acid metabolising enzymes CYP 26A1, CYP26B1 and LRAT are significantly overexpressed in colorectal cancer and that CYP25B1, LRAT andLRAT are significant associated with prognosis both in the total cohort and in those tumours which are mismatch repair proficient. Expand
Applications de la spectrométrie de masse aux études du métabolisme et à la pharmacodynamie des immunosuppresseurs
Ces travaux de these s’inscrivaient dans l’etude par la spectrometrie de masse de la pharmacodynamie, dont l’objectif est de caracteriser des effets biochimiques et physiologiques des medicaments surExpand
Using in vitro methods to determine P450s responsible for metabolism and discrimination from other oxidative pathways
This chapter will provide an overview on how to identify which P450s are involved in the metabolism of a compound, discrimination of P450 vs non-P450 metabolic routes, and examples of the physiological-based pharmacokinetic models that were used in risk assessment. Expand
13. Reaction Phenotyping


Polymorphism of cytochrome P450 and xenobiotic toxicity.
Recent aspects of cytochrome P450 polymorphism and xenobiotic toxicity are discussed and no firm relationships have been established linking increased risk for cancer with any specific P450 SNP. Expand
Cytochrome P450 pharmacogenetics in drug development: in vitro studies and clinical consequences.
Current trends in the industry have been fueled by increased managed healthcare, the desire to minimize the need for therapeutic drug monitoring and CYP genotyping in medical practice, and a very competitive market place. Expand
Monoclonal Antibodies and Multifunctional Cytochrome P450: Drug Metabolism as Paradigm
The unique and precise specificity and high inhibitory activity toward individual cytochrome P450s make the monoclonal antibodies extraordinary tools for identifying and quantifying the role of each P450 isoform in the metabolism of a drug or nondrug xenobiotic. Expand
Cytochrome P450 in vitro reaction phenotyping: a re-evaluation of approaches used for P450 isoform identification.
Reevaluated various approaches used to identify P450 isoform(s) responsible for the metabolism of therapeutic agents and found that in well conducted in vitro experiments, isoform-selective chemical inhibitors can also provide valuable and reliable information. Expand
Characterisation of the xenobiotic-metabolizing Cytochrome P450 expression pattern in human lung tissue by immunochemical and activity determination.
In preparing for studying factors to explain interindividual variability of CYP expression in lung tissue, methodologies to quantify a panel of CYp enzymes in human lung samples are established among which there are CYP enzymes whose expression at the protein and activity level has not been evidenced so far. Expand
Inhibition kinetics of monoclonal antibodies against cytochromes P450.
The results have demonstrated that the model can accurately predict the kinetic parameters and provide some insights into the understanding of the mechanism of MAb interaction with P450 enzyme in nature and the applications of the MAbs in qualitative and quantitative identification of P450s involved in drug metabolism. Expand
Use of inhibitory monoclonal antibodies to assess the contribution of cytochromes P450 to human drug metabolism.
In inhibitory monoclonal antibodies could play a unique role in defining the single or subfamily of cytochrome P450 that is responsible for the metabolism of specific drugs. Expand
Inhibition and Induction of Cytochrome P450 and the Clinical Implications
T careful evaluation of potential drug interactions of a new drug candidate during the early stage of drug development is essential, because the smaller the difference between toxic and effective concentration, the greater the likelihood that a drug interaction will have serious clinical consequences. Expand
Evaluation of Recombinant Cytochrome P450 Enzymes as an in Vitro System for Metabolic Clearance Predictions
Recombinant enzymes demonstrated improved prediction reliability relative to HLMs and hepatocytes, and the most reliable correlations in terms of lowest bias and highest precision were observed by comparing in vivo CLint, calculated using the parallel-tube model and incorporating fraction unbound in blood. Expand
A monoclonal antibody inhibitory to human P450 2D6: a paradigm for use in combinatorial determination of individual P450 role in specific drug tissue metabolism.
These studies demonstrate that inhibitory monoclonal antibodies offer a simple and precise method for assessing the quantitative role of each P450 in the metabolism of a P450 substrate in a tissue, which include drugs, carcinogens, mutagens, toxic chemicals and endobiotics. Expand