Coumarins are competitive inhibitors of cytochrome P450 1B1, with equal potency for allelic variants

Jennifer S Mammen, Heather E. Kleiner, John DiGiovanni, Thomas R. Sutter, Paul Timothy Strickland

Research output: Contribution to journalArticle

Abstract

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 K i values equal to 587, 11, 6 and 1 μM 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.

Original languageEnglish (US)
Pages (from-to)183-188
Number of pages6
JournalPharmacogenetics and Genomics
Volume15
Issue number3
StatePublished - Mar 2005

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Coumarins
Cytochrome P-450 Enzyme System
Enzymes
Haplotypes
Asian Americans
Benzo(a)pyrene
Microsomes
African Americans
Carcinogens
Yeasts
Amino Acids

Keywords

  • Allelic variants
  • Benzo[a]pyrene
  • Chemoprevention
  • Coumarin
  • Cytochrome P450 1B1

ASJC Scopus subject areas

  • Genetics
  • Pharmacology

Cite this

Coumarins are competitive inhibitors of cytochrome P450 1B1, with equal potency for allelic variants. / Mammen, Jennifer S; Kleiner, Heather E.; DiGiovanni, John; Sutter, Thomas R.; Strickland, Paul Timothy.

In: Pharmacogenetics and Genomics, Vol. 15, No. 3, 03.2005, p. 183-188.

Research output: Contribution to journalArticle

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AU - Kleiner, Heather E.

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AU - Strickland, Paul Timothy

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N2 - 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 K i values equal to 587, 11, 6 and 1 μM 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.

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