Monoclonal Antibodies and Multifunctional Cytochrome P450: Drug Metabolism as Paradigm

@article{Gelboin2006MonoclonalAA,
  title={Monoclonal Antibodies and Multifunctional Cytochrome P450: Drug Metabolism as Paradigm},
  author={H. V. Gelboin and Kristopher W. Krausz},
  journal={The Journal of Clinical Pharmacology},
  year={2006},
  volume={46}
}
Monoclonal antibodies are reagents par excellence for analyzing the role of individual cytochrome P450 isoforms in multifunctional biological activities catalyzed by cytochrome P450 enzymes. The precision and utility of the monoclonal antibodies have heretofore been applied primarily to studies of human drug metabolism. The unique and precise specificity and high inhibitory activity toward individual cytochrome P450s make the monoclonal antibodies extraordinary tools for identifying and… Expand
Antibodies as a Probe in Cytochrome P450 Research
TLDR
The inhibitory antibodies are uniquely suited for reaction phenotyping that helps to predict human pharmacokinetics for clinical drug-drug interaction potential in drug discovery and development and for implications in pharmacogenetics and human risk assessment. Expand
Cytochrome P450 reaction-phenotyping: an industrial perspective
TLDR
In vitro CYP reaction-phenotyping and the integration of data are focused on and relatively simple strategies enabling the design and prioritization of follow up clinical studies are discussed. Expand
Using in vitro methods to determine P450s responsible for metabolism and discrimination from other oxidative pathways
TLDR
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
Distinction between human cytochrome P450 (CYP) isoforms and identification of new phosphorylation sites by mass spectrometry.
TLDR
The performance of a mass spectrometry-based strategy to simultaneously detect and differentiate distinct human Cytochrome P450 (CYP) isoforms including the highly similar CYP3A4, CYP 3A5, CYp3A7, as well as CYP2C8, CYB2C9, CYC2C18, CYF2C19, and CYP4F2 is demonstrated. Expand
Involvement of Multiple Cytochrome P450 and UDP-Glucuronosyltransferase Enzymes in the in Vitro Metabolism of Muraglitazar
TLDR
This study describes the identification of human cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) enzymes involved in the in vitro metabolism of muraglitazar, a dual α/γ peroxisome proliferator-activated receptor activator that has both glucose- and lipid-lowering effects in animal models and in patients with diabetes. Expand
The Endocannabinoid Anandamide Is a Substrate for the Human Polymorphic Cytochrome P450 2D6
TLDR
This study suggests that anandamide may be a physiological substrate for brain mitochondrial CYP2D6, implicating this polymorphic enzyme as a potential component of the endocannabinoid system in the brain and offers support to the hypothesis that neuropsychiatric phenotype differences among individuals with genetic variations in CYP1D6 could be ascribable to interactions of this enzyme with endogenous substrates. Expand
Utility of polyclonal antibodies targeted toward unique tryptic peptides in the proteomic analysis of cytochrome P450 isozymes.
TLDR
Three different immunochemical techniques have potential to be incorporated in an integrated proteomic method combining mass spectrometry and immunochemistry that has been developed in the laboratory over the last several years. Expand
Expression of CYP4F2 in human liver and kidney: assessment using targeted peptide antibodies.
TLDR
Immunoquantitation and correlation analyses performed with this antibody suggest that CYP4F2 functions as a predominant LTB4 and arachidonate omega-hydroxylase in human liver. Expand
Roles of different CYP enzymes in the formation of specific fluvastatin metabolites by human liver microsomes.
TLDR
The results suggest that M-2 and M-5 are formed preferentially by CYP2C9, and thatM-3 is mainly formed by CYp3A. Expand
Identification of the Oxidative and Conjugative Enzymes Involved in the Biotransformation of Brivanib
TLDR
Overall, multiple enzymes are involved in the metabolism of brivanib, suggesting a low potential for drug-drug interactions either through polymorphism or through inhibition of a particular drug-metabolizing enzyme. Expand
...
1
2
3
...

References

SHOWING 1-10 OF 59 REFERENCES
A monoclonal antibody inhibitory to human P450 2D6: a paradigm for use in combinatorial determination of individual P450 role in specific drug tissue metabolism.
TLDR
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
Inhibition kinetics of monoclonal antibodies against cytochromes P450.
TLDR
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
Inhibitory monoclonal antibodies to human cytochrome P450 1A2: analysis of phenacetin O-deethylation in human liver.
TLDR
The use of inhibitory MAbs to P450s is demonstrated for a simple and precise assessment of the quantitative role of each P450 in the metabolism of substrates, including drugs, carcinogens, mutagens, environmental chemicals and endobiotics. Expand
Cytochrome P450 in vitro reaction phenotyping: a re-evaluation of approaches used for P450 isoform identification.
TLDR
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
Monoclonal antibodies specific and inhibitory to human cytochromes P450 2C8, 2C9, and 2C19.
TLDR
The mAb system offers large potential for studies of cytochrome P450 function useful in drug discovery and reduces the possibility of adverse drug reactions due to polymorphisms and drug interactions. Expand
An inhibitory monoclonal antibody to human cytochrome P450 2A6 defines its role in the metabolism of coumarin, 7-ethoxycoumarin and 4-nitroanisole in human liver.
TLDR
The degree of inhibition defines the contribution of CYP2A6 activity to the 4-nitroanisole and 7-ethoxycoumarin metabolism in human liver and the range reflects the variability among samples. Expand
Inhibitory and non-inhibitory monoclonal antibodies to human cytochrome P450 3A3/4.
TLDR
MAb 3-29-9 has been used successfully to measure the quantitative contribution of P450 3A3 and 3A4 to the metabolism of the above-designated substrates in human adult liver. Expand
Monoclonal antibodies to rabbit liver cytochrome P450 LM2
TLDR
Each isozyme of P450 exhibits stereoselectivity in substrate choice and product formation with respect to both benzo[a]pyrene metabolism and the conversion of (-)t-7,8-diol benzo’s pyrene into the highly mutagenic benzo [a] pyrene 7,&diol9,1 Oepoxides. Expand
Inhibitory monoclonal antibody to human cytochrome P450 2B6.
TLDR
This study is a prototype for the use of specific and highly inhibitory MAbs to determine individual P450 function and determines the contribution of 2B6 to the metabolism of its substrates in a human tissue containing multiple P450s. Expand
Monoclonal antibody phenotyping of interindividual differences in cytochrome P-450-dependent reactions of single and twin human placenta.
TLDR
The placentas from both dizygotic and dichorionic monozygotic twins show extraordinarily high intrapair concordance for both the absolute amounts of AHH and ECD and their inhibition by MAb 1-7-1 compared with unrelated individuals, indicating that interindividual differences in these parameters of biological activity are not due to random variation or experimental error. Expand
...
1
2
3
4
5
...