| An inhibitory monoclonal antibody to human cytochrome P450 that specifically binds and inhibits P4502C9II, an allelic variant of P4502C9 having a single amino acid change Arg144 Cys. | |
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MedLine Citation:
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PMID: 10923863 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A monoclonal antibody (MAb 292-2-3) has been isolated that binds specifically to a single allele of three expressed human cytochrome P4502C9 alleles. The MAb binds to 2C9Cys144 (II), and does not bind to the wild-type 2C9Arg144 (I), or the third allele 2C9Ile-->Leu359 (III) and thus the MAb detects an allele with > 99% homology and differing from the wild-type 2C9Arg144 (I) by a single amino acid. The MAb 292-2-3 does not bind to the other 2C isoforms (2C8, 2C18, 2C19) or the other human cytochrome P450s, 1A1, 1A2, 2A6, 2B6, 2C8, 2D6, 2E1 or 3A4/5. MAb 292-2-3 inhibits the metabolism of tolbutamide, diclofenac and phenanthrene by the target 2C9Cys144 (II) allele by > 90% and does not inhibit the catalytic activity of the wild-type 2C9Arg144 (I), or 2C9Ile-->Leu359 (III) the other 2C isoforms 2C8, 2C18, 2C19, or the other non-2C human P450s listed above. The MAb 292-2-3 is thus a prototype of an ideal and extraordinarily specific reagent for the detection and measurement of the metabolic role of highly related isoforms and polymorphic alleles of human cytochrome P450s. MAbs of high specificity can also determine the amount of phenotypic expression of polymorphic alleles and their metabolic role in drug and non-drug xenobiotic metabolism in heterozygote individuals. The inhibitory MAb might also identify allele-specific substrates of polymorphic human cytochrome P450s. |
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Authors:
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K W Krausz; I Goldfarb; T J Yang; F J Gonzalez; H V Gelboin |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Xenobiotica; the fate of foreign compounds in biological systems Volume: 30 ISSN: 0049-8254 ISO Abbreviation: Xenobiotica Publication Date: 2000 Jun |
Date Detail:
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Created Date: 2000-12-13 Completed Date: 2000-12-13 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 1306665 Medline TA: Xenobiotica Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 619-25 Citation Subset: IM |
Affiliation:
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Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alleles Amino Acid Substitution / genetics* Antibodies, Monoclonal / immunology*, pharmacology* Antibody Specificity* Arginine / genetics, metabolism Aryl Hydrocarbon Hydroxylases* Cysteine / genetics, metabolism Cytochrome P-450 Enzyme System / antagonists & inhibitors*, genetics, immunology*, metabolism Diclofenac / metabolism Enzyme-Linked Immunosorbent Assay Genetic Variation / genetics Humans Hybridomas Isoenzymes / antagonists & inhibitors, genetics, immunology, metabolism Phenanthrenes / metabolism Polymorphism, Genetic / genetics, immunology Protein Binding / genetics, immunology Recombinant Proteins / antagonists & inhibitors, immunology, metabolism Steroid 16-alpha-Hydroxylase* Steroid Hydroxylases / antagonists & inhibitors*, genetics, immunology*, metabolism Tolbutamide / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal; 0/Isoenzymes; 0/Phenanthrenes; 0/Recombinant Proteins; 15307-86-5/Diclofenac; 52-90-4/Cysteine; 64-77-7/Tolbutamide; 74-79-3/Arginine; 85-01-8/phenanthrene; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.-/Steroid Hydroxylases; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/Steroid 16-alpha-Hydroxylase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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