title: 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.
authors: Institute of Toxicology, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacherstr. 67, 55131, Mainz, Germany.
authors: Dagmar
authors: D
authors: Faust
authors: Institute of Toxicology, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacherstr. 67, 55131, Mainz, Germany.
authors: Teodora
authors: T
authors: Nikolova
authors: Institute of Agricultural and Nutritional Sciences, Martin-Luther University Halle-Wittenberg, Weinbergweg 22, 06120, Halle (Saale), Germany.
authors: Wim
authors: W
authors: Wätjen
authors: Institute of Toxicology, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacherstr. 67, 55131, Mainz, Germany.
authors: Bernd
authors: B
authors: Kaina
authors: Institute of Toxicology, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacherstr. 67, 55131, Mainz, Germany. cdietric@uni-mainz.de.
authors: Cornelia
authors: C
authors: Dietrich
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D001937:Brassica / Q000737:chemistry*; D018938:Caco-2 Cells / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D053960:DNA Breaks / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010084:Oxidation-Reduction; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
chemical_list: C497396:ARNT protein, human; D002227:Carbazoles; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D020011:Protective Agents; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C075954:indolo(3,2-b)carbazole
keywords: Aryl hydrocarbon receptor; Indolo[3,2-b]carbazole; Oxidative DNA damage; Protection