Quercetin and Isorhamnetin Reduce Benzo[a]pyrene-Induced Genotoxicity by Inducing RAD51 Expression through Downregulation of miR−34a

Abstract

Benzo[a]pyrene (B[a]P) is metabolized in the liver into highly reactive mutagenic and genotoxic metabolites, which induce carcinogenesis. The mutagenic factors, including B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE) and reactive oxygen species, generated during B[a]P metabolism can cause DNA damage, such as BPDE-DNA adducts, 8-oxo-dG, and double-strand breaks (DSBs). In this study, we mechanistically investigated the effects of quercetin and its major metabolite isorhamnetin on the repair of B[a]P-induced DNA DSBs. Whole−transcriptome analysis showed that quercetin and isorhamnetin each modulate the expression levels of genes involved in DNA repair, especially those in homologous recombination. RAD51 was identified as a key gene whose expression level was decreased in B[a]P−treated cells and increased by quercetin or isorhamnetin treatment. Furthermore, the number of γH2AX foci induced by B[a]P was significantly decreased by quercetin or isorhamnetin, whereas RAD51 mRNA and protein levels were increased. Additionally, among the five microRNAs (miRs) known to downregulate RAD51, miR−34a level was significantly downregulated by quercetin or isorhamnetin. The protective effect of quercetin or isorhamnetin was lower in cells transfected with a miR−34a mimic than in non−transfected cells, and the B[a]P-induced DNA DSBs remained unrepaired. Our results show that quercetin and isorhamnetin each upregulates RAD51 by downregulating miR−34a and thereby suppresses B[a]P-induced DNA damage.

Effects of Quercetin Nanoemulsion on Cholesterol Efflux and MicroRNA-33/34a Expression in the Liver of Mice Fed with a High-Cholesterol Diet

“…Therefore, the roles of miR-33, and miR-34a in cholesterol metabolism may be potential biomarkers in atherosclerosis. Recently, Kim et al (2022) have reported that quercetin and its metabolite, isorhamnetin, suppress liver DNA damage via miR-34a downregulation in HepG2 cells. However, QN’s effects on the regulatory mechanisms of miR-33 and miR-34a in the liver of HC diet-fed mice are yet to be elucidated.…”

Chronic Exposure to TDI Induces Cell Migration and Invasion via TGF-β1 Signal Transduction

“…Transcriptome analyses were performed adhering to previous research [ 51 , 52 ]. Gene ontology (GO) analysis of DEGs (fold change ≥ 2; normalized log 2 ≥ 5) was performed.…”