title: CYP1A1 genotype-selective inhibition of benzo[a]pyrene activation by quercetin.
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.
authors.affiliation: Institute of Clinical Pharmacology, Charité-University Medicine Berlin, Humboldt University of Berlin, D-10098 Berlin, Germany. dieter.schwarz@charite.de
authors.forename: Dieter
authors.initials: D
authors.lastname: Schwarz
authors.forename: Pyotr
authors.initials: P
authors.lastname: Kisselev
authors.forename: Ivar
authors.initials: I
authors.lastname: Roots
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002273:Carcinogens / Q000037:antagonists & inhibitors; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D011794:Quercetin / Q000494:pharmacology*
chemical_list: D002273:Carcinogens; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D011794:Quercetin; D019363:Cytochrome P-450 CYP1A1