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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.
Xenobiotica. 2000 Jun; 30(6):619-25.X

Abstract

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.

Authors+Show Affiliations

Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10923863

Citation

Krausz, K W., et al. "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." Xenobiotica; the Fate of Foreign Compounds in Biological Systems, vol. 30, no. 6, 2000, pp. 619-25.
Krausz KW, Goldfarb I, Yang TJ, et al. 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. Xenobiotica. 2000;30(6):619-25.
Krausz, K. W., Goldfarb, I., Yang, T. J., Gonzalez, F. J., & Gelboin, H. V. (2000). 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. Xenobiotica; the Fate of Foreign Compounds in Biological Systems, 30(6), 619-25.
Krausz KW, et al. 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. Xenobiotica. 2000;30(6):619-25. PubMed PMID: 10923863.
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TY - JOUR T1 - 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. AU - Krausz,K W, AU - Goldfarb,I, AU - Yang,T J, AU - Gonzalez,F J, AU - Gelboin,H V, PY - 2000/8/3/pubmed PY - 2001/2/28/medline PY - 2000/8/3/entrez SP - 619 EP - 25 JF - Xenobiotica; the fate of foreign compounds in biological systems JO - Xenobiotica VL - 30 IS - 6 N2 - 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. SN - 0049-8254 UR - https://www.unboundmedicine.com/medline/citation/10923863/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_ L2 - https://www.tandfonline.com/doi/full/10.1080/004982500406444 DB - PRIME DP - Unbound Medicine ER -