title: Coumarins are competitive inhibitors of cytochrome P450 1B1, with equal potency for allelic variants.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Mammen
authors.forename: Heather E
authors.initials: HE
authors.lastname: Kleiner
authors.forename: John
authors.initials: J
authors.lastname: DiGiovanni
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Sutter
authors.forename: Paul T
authors.initials: PT
authors.lastname: Strickland
mesh_terms: D000483:Alleles; D000596:Amino Acids / Q000737:chemistry; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001483:Base Sequence; D001667:Binding, Competitive; D003374:Coumarins / Q000378:metabolism / Q000494:pharmacology*; D065633:Cytochrome P-450 CYP1B1; D018076:DNA, Complementary / Q000378:metabolism; D004101:Dihydroxydihydrobenzopyrenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D011564:Furocoumarins / Q000494:pharmacology; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010100:Oxygen / Q000378:metabolism; D011110:Polymorphism, Genetic
chemical_list: D000596:Amino Acids; D016588:Anticarcinogenic Agents; D003374:Coumarins; D018076:DNA, Complementary; D004101:Dihydroxydihydrobenzopyrenes; D011564:Furocoumarins; C055542:isoimperatorin; C017228:benzo(a)pyrene 7,8-dihydrodiol; C015304:isopimpinellin; C030123:coumarin; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; C068337:bergamottin; C031534:imperatorin; D010100:Oxygen