The Brassica-derived phytochemical indolo[3,2-b]carbazole protects against oxidative DNA damage by aryl hydrocarbon receptor activation

Abstract

Epidemiological studies suggest that a high intake of Brassica vegetables protects against colon carcinogenesis. Brassica vegetables are rich in glucosinolates which are hydrolysed during digestion to various products including indole-3-carbinol. In animal studies, a protective effect of indole-3-carbinol has been demonstrated in colon carcinogenesis. Indole-3-carbinol is highly unstable and, therefore, the observed protection likely results from condensation products of indole-3-carbinol, e.g. diindolylmethane or indolo[3,2-b]carbazole (ICZ). Interestingly, ICZ is a potent activator of the aryl hydrocarbon receptor (AhR), a transcription factor known to mediate toxic effects of environmental pollutants, such as dioxin and polycyclic aromatic hydrocarbons. Here, we show that ICZ protects against oxidative DNA damage in various cell lines including the colon carcinoma cell line Caco-2. When preincubated for 24 h, ICZ decreases DNA single-strand break (SSB) and 8-oxo-dG formation induced by tertiary-butylhydroperoxide (t-BOOH), hydrogen peroxide or benzo[a]pyrene. Simultaneous addition of ICZ does not protect against t-BOOH-induced SSB formation, which disproves a direct radical scavenging effect. The repair of SSBs was not enhanced, but the data indicate that ICZ attenuates the ROS level following t-BOOH. The antioxidant response factor Nrf2 was not activated following ICZ. Functional inhibition of the AhR and AhR-/ARNT-defective cell lines demonstrate that the AhR/ARNT pathway is mandatory for the observed ROS defence caused by ICZ, supporting the hypothesis that AhR-mediated regulation of defence genes is involved. The data point to a hitherto unknown protective function of ICZ and a novel role of the AhR in the defence against oxidative DNA damage.

Antioxidant Functions of the Aryl Hydrocarbon Receptor

“…Protective mechanisms keeping the level of oxidatively damaged DNA low, despite the generation of oxidative stress, would also explain the lack of TCDD-mediated mutagenicity in rats [101]. In view of the well-known cell type and organ specificity of AhR function, it is plausible to assume that, depending on the cell type or organ, oxidative or antioxidative AhR pathways predominate [67]. …”

“…Since both B[ a ]P and hydrogen peroxide lead to an increase in intracellular ROS formation [20, 66] (and our own unpublished data), the data suggest an antioxidant function of ICZ. We deeply investigated a potential antioxidant effect of ICZ and revealed that ICZ protects against oxidative DNA damage in various cell lines, including the colon carcinoma cell line Caco-2 [67]. ICZ decreased DNA single-strand breaks (SSB) and 8-oxo-2′-deoxyguanosine (8-oxo-dG) formation induced by hydrogen peroxide, tertiary-butyl-hydroperoxide (t-BOOH), or B[ a ]P when preincubated for 24 h. We found that intracellular ROS levels were attenuated following t-BOOH exposure.…”

Genoprotective activities of plant natural substances in cancer and chemopreventive strategies in the context of 3P medicine

“…It was demonstrated that ICZ activated AhR being protective against oxidative DNA damage in Caco-2 cells. The results suggest that the AhR-dependent pathway was associated with protective activity against ROS-induced DNA damage in colorectal carcinogenesis, and was independent of the Nrf2 pathway [20].…”

“…As such, introducing new clinical approaches reducing cancer risks would be highly beneficial for healthcare as a whole. To this end, instability of DNA structure as critical aspect of carcinogenesis under certain conditions can be chemoprevented by plant-derived bioactive compounds (phytochemicals) resulting in reduced risks of cancer development [18][19][20][21][22][23][24][25][26]. This review highlights central mechanisms of phytochemicals as natural genoprotectors, presents a spectrum of their anticancer properties, and considers their potential application for individuals at risk and patients in the context of 3P medicine, namely, predictive diagnostics, targeted primary and secondary prevention, and personalisation of treatments.…”

Effects of the Ser326Cys Polymorphism in the DNA Repair OGG1 Gene on Cancer, Cardiovascular, and All-Cause Mortality in the PREDIMED Study: Modulation by Diet

“…The MedDiet is characterized by a high intake of vegetables 37,65 . Vegetables are very rich in antioxidants and other phytochemicals 66,67 that may contribute to a better DNA protection from oxidation in Cys326Cys individuals who have less capacity for repairing it [68][69][70] . Recent metaanalyses 71,72 have shown that high vegetable consumption is associated with a lower risk of allcause mortality 71,72 , particularly cardiovascular mortality 72 .…”