Quercetin and Isorhamnetin Attenuate Benzo[a]pyrene-Induced Toxicity by Modulating Detoxification Enzymes through the AhR and NRF2 Signaling Pathways

Abstract

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.

Alpinetin inhibits macrophage infiltration and atherosclerosis by improving the thiol redox state: Requirement of GSk3β/Fyn‐dependent Nrf2 activation

“…In the present study, we investigated the role of alpinetin in macrophage/endothelial adhesion and monocyte intimal infiltration, and we analyzed its protective function in the development of atherosclerotic plaques. Given that other flavonoids, such as narigenin, 25 epicatechin, 26 and quercetin, 27 have been demonstrated to enhance antioxidant defense by regulating Nrf2, and that puerarin 28 and procyanidin 29 are effective GSK‐3β modulators, we further explored whether the beneficial effects of alpinetin are dependent on GSK‐3β/Nrf2‐mediated redox restoration.…”

Quercetin Attenuates Quinocetone-Induced Cell Apoptosis In Vitro by Activating the P38/Nrf2/HO-1 Pathway and Inhibiting the ROS/Mitochondrial Apoptotic Pathway

“…[ 28 ]. Moreover, several studies found that quercetin supplementation could significantly reduce hepatotoxicity and nephrotoxicity caused by antibacterial drugs (e.g., rifampicin and ciprofloxacin) or environmental toxins (e.g., copper, nickel, ochratoxin A, and benzo(a)pyrene) by inhibiting oxidative stress and the inflammatory response [ 29 , 30 , 31 , 32 , 33 ]. Currently, there is limited information on whether quercetin could provide the protective effects on QCT-induced cytotoxicity.…”

Green sweet potato leaves increase Nrf2-mediated antioxidant activity and facilitate benzo[a]pyrene metabolism in the liver by increasing phase II detoxifying enzyme activities in rats

“…12,13 Recent studies indicated that flavonoids (e.g., quercetin) can lower B[a]P-induced toxicity by increasing the expression of phase II conjugation enzymes and membrane transporters. 14 Sweet potato (Ipomoea batatas L.) is an important food crop from the Convolvulaceae family that has about 6500 varieties worldwide. 15 The sweet potato plant tolerates flooding and is resistant to pests 16,17 and provides various nutrients that can compensate for malnutrition and vitamin deficiencies.…”

“…, quercetin) can lower B[ a ]P-induced toxicity by increasing the expression of phase II conjugation enzymes and membrane transporters. 14…”