Coumarins are competitive inhibitors of cytochrome P450 1B1, with equal potency for allelic variants.
Mammen-JS; Kleiner-HE; DiGiovanni-J; Sutter-TR; Strickland-PT
Pharmacogenet Genomics 2005 Mar; 15(3):183-188
OBJECTIVES: Coumarins are naturally occurring chemicals with potential as chemopreventive agents, several with known action on the cytochrome P450 1A family. We examined whether cytochrome P450 1B1 (CYP1B1) was inhibited by coumarins, whether such inhibition was competitive, and whether inhibition varied between common polymorphic variants of this enzyme. METHODS: We tested the inhibition properties of four coumarins, bergamottin, isopimpinellin, isoimperatorin, and imperatorin in an assay for oxidation of (-)benzo[a]pyrene-7R-trans-7,8-dihyrodiol (B[a]P-7,8-diol) by CYP1B1 using yeast-microsome expressed enzymes. These assays were performed with wild-type enzyme and five single-amino acid polymorphic variants. RESULTS: All four coumarins are competitive inhibitors of CYP1B1, with Ki values equal to 587, 11, 6 and 1 muM respectively. Inhibition parameters were consistent between five haplotypes of CYP1B1, three representing common haplotypes in Asians, African-Americans and European-Americans, and two with baseline kinetic parameters previously shown to be potentially different from wild-type. CONCLUSIONS: Coumarins are capable of inhibiting carcinogen activation by CYP1B1 with varying potencies, and their efficacy as chemopreventive agents is not likely to be affected by polymorphism in this enzyme.
Amino-acids; Chemical-binding; Pharmacology; Metabolism; Genetics; Humans; Kinetics; Microsomal-enzymes; Pharmacology;
Author Keywords: Cytochrome P450 1B1; Coumarin; Chemoprevention; Benzo[a]pyrene; Allelic variants
Paul T. Strickland, Johns Hopkins, Bloomberg School of Public Health, 615 N Wolfe Street, Room E7535, Baltimore MD, 21205
Pharmacogenetics and Genomics
Johns Hopkins University