Abstract
Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon, is a group 1 carcinogen that introduces mutagenic DNA adducts into the genome. In this study, we investigated the molecular mechanisms underlying the involvement of silymarin in the reduction of DNA adduct formation by B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE), induced by B[a]P. B[a]P exhibited toxicity in HepG2 cells, whereas co-treatment of the cells with B[a]P and silymarin reduced the formation of BPDE-DNA adducts, thereby increasing cell viability. Determination of the level of major B[a]P metabolites in the treated cells showed that BPDE levels were reduced by silymarin. Nuclear factor erythroid 2-related factor 2 (Nrf2) and pregnane X receptor (PXR) were found to be involved in the activation of detoxifying genes against B[a]P-mediated toxicity. Silymarin did not increase the expression of these major transcription factors, but greatly facilitated their nuclear translocation. In this manner, treatment of HepG2 cells with silymarin modulated detoxification enzymes through NRF2 and PXR to eliminate B[a]P metabolites. Knockdown of Nrf2 abolished the preventive effect of silymarin on BPDE-DNA adduct formation, indicating that activation of the Nrf2 pathway plays a key role in preventing B[a]P-induced genotoxicity. Our results suggest that silymarin has anti-genotoxic effects, as it prevents BPDE-DNA adduct formation by modulating the Nrf2 and PXR signaling pathways.
Highlights
Benzo[a]pyrene (B[a]P) is a ubiquitous environmental pollutant produced during incomplete combustion from sources such as diesel engine exhaust, cigarette smoke, and industrial activities
We show the effect of silymarin on the reduction of genotoxicity through the regulation of B[a]P metabolites and the reduction of BPDE-DNA adduct formation via the modulation of Nuclear factor erythroid 2-related factor 2 (Nrf2) and pregnane X receptor (PXR) signaling pathways
To confirm that silymarin regulates the Nrf2 signaling pathway, which is related to the attenuation of BPDE-DNA adduct formation, we demonstrated that knockdown of Nrf2 expression by RNA interference abolishes the inhibition of BPDE-DNA adduct formation by silymarin (Figure 5B)
Summary
Benzo[a]pyrene (B[a]P) is a ubiquitous environmental pollutant produced during incomplete combustion from sources such as diesel engine exhaust, cigarette smoke, and industrial activities. B[a]P is produced during certain types of food processing such as grilling and broiling [1]. It is classified by the International Agency for Research on Cancer (IARC) as a group I carcinogen [2,3]. Prolonged exposure to B[a]P accelerates metastasis and angiogenesis in the liver and induces cancer in the liver, lungs, skin, cervix, and the gastrointestinal tract (colorectal and stomach) [4,5,6,7]. After exposure to B[a]P, cellular cytochrome P450 (CYP) metabolizes B[a]P to B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE), which interacts with DNA to form carcinogenic BPDE-DNA adducts in vitro and in vivo [11,12,13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
