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Benzo[a]pyrene, classified as a Group 1 carcinogen, is metabolized to B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE), causing DNA mutations and eventually cancer. Quercetin is a dietary flavonoid abundant in fruits and vegetables. After quercetin intake, quercetin’s metabolites isorhamnetin and miquelianin are more highly concentrated than quercetin in the human plasma. In this study, we investigated the molecular mechanisms associated with the cytoprotective effect of quercetin and its metabolites against benzo[a]pyrene from a detoxification perspective. Quercetin and its metabolite isorhamnetin reduced benzo[a]pyrene-induced cytotoxicity, whereas the metabolite miquelianin did not mitigate benzo[a]pyrene-induced cytotoxicity. Moreover, quercetin and isorhamnetin reduced intracellular levels of BPDE-DNA adducts. The formation and elimination of BPDE is mediated by the xenobiotic detoxification process. Quercetin and isorhamnetin increased the gene and protein expression levels of phase I, II, and III enzymes involved in xenobiotic detoxification. Furthermore, quercetin and isorhamnetin induced the translocation of aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (NRF2), which regulate the expression level of phase enzymes. Our results suggest that quercetin and isorhamnetin promote the metabolism, detoxification, and elimination of B[a]P, thereby increasing anti-genotoxic effects and protecting against B[a]P-induced cytotoxicity.

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Benzo[a]pyrene (B[a]P), a group 1 carcinogen, induces mutagenic DNA adducts. Myricetin is present in many natural foods with diverse biological activities, such as anti-oxidative and anti-cancer activities. The aim of this study was to investigate the protective effects of myricetin against B[a]P-induced toxicity. Treatment of B[a]P induced cytotoxicity on HepG2 cells, whereas co-treatment of myricetin with B[a]P reduced the formation of the B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE)-DNA adduct, which recovered cell viability. Furthermore, we found a protective effect of myricetin against B[a]P-induced genotoxicity in rats, via myricetin-induced inhibition of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and BPDE-DNA adduct formation in the liver, kidney, colon, and stomach tissue. This inhibition was more prominent in the liver than in other tissues. Correspondingly, myricetin regulated the phase I and II enzymes that inhibit B[a]P metabolism and B[a]P metabolites conjugated with DNA by reducing and inducing CYP1A1 and glutathione S-transferase (GST) expression, respectively. Taken together, this showed that myricetin attenuated B[a]P-induced genotoxicity via regulation of phase I and II enzymes. Our results suggest that myricetin is anti-genotoxic, and prevents oxidative DNA damage and BPDE-DNA adduct formation via regulation of phase I and II enzymes.