CYP1A1 genotype-selective inhibition of benzo[a]pyrene activation by quercetin

Eur J Cancer. 2005 Jan;41(1):151-8. doi: 10.1016/j.ejca.2004.08.011.

Abstract

Epidemiological studies suggest that food rich in quercetin and naringin may protect against certain types of lung cancer, and that genotype dependent inhibition of cytochrome P450 1A1 (CYP1A1)-mediated bioactivation of procarcinogens could be the underlying mechanism. We studied the inhibitory effects of quercetin and naringin on the terminal bioactivation step of benzo[a]pyrene (B[a]P), a member of the major class of lung carcinogens. This reaction (epoxidation of (+/-)-trans-7,8-dihydro-7,8-dihydroxy-B[a]P to the ultimate carcinogenic product, (+/-)-B[a]P-r-7,t-8-dihydrodiol-t-9,10-epoxide (diolepoxide 2)) was examined using three of the most common allelic variants of human CYP1A1, namely wild-type CYP1A1.1, CYP1A1.2, and CYP1A1.4. Quercetin potently inhibited diolepoxide 2 formation by all CYP1A1 types with IC(50) values between 1.6 and 7.0 microM. The differences between the wild-type enzyme and the variants were statistically highly significant (P < 0.01). Enzyme kinetics revealed quercetin as a mixed-type inhibitor of CYP1A1.1, CYP1A1.2, and CYP1A1.4 with K(i) values of 2.0, 6.4, and 9.3 microM, respectively. Naringin inhibited diolepoxide 2 formation only slightly. Our data support the hypothesis that quercetin may have a stronger chemopreventive effect in individuals carrying wild-type compared with variant CYP1A1 genes. Future studies should consider the influence of P450 polymorphisms on both procarcinogen activation and its inhibition to facilitate the development of genotype-specific chemoprevention regimes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / metabolism
  • Benzo(a)pyrene / antagonists & inhibitors*
  • Benzo(a)pyrene / metabolism
  • Carcinogens / antagonists & inhibitors
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP1A1 / genetics*
  • Genotype
  • Humans
  • Lung Neoplasms / genetics*
  • Quercetin / pharmacology*

Substances

  • Carcinogens
  • Benzo(a)pyrene
  • 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
  • Quercetin
  • Cytochrome P-450 CYP1A1