title: The broccoli-born isothiocyanate sulforaphane impairs nucleotide excision repair: XPA as one potential target.
abstract: The isothiocyanate sulforaphane (SFN), the major hydrolysis product of glucosinolates present in broccoli, has frequently been proposed to exert anticarcinogenic properties, mainly due to the induction of the nrf2/Keap1/ARE-signaling pathway. As potential underlying mechanism, a SFN-dependent zinc release from Keap1, the negative regulator of nrf2, has been described. This raises the question whether SFN is able to interfere with other zinc binding structures as well, for example those essential for DNA repair. Within this study, a SFN-induced deliberation of zinc from a synthesized peptide resembling the zinc binding domain of the xeroderma pigmentosum A (XPA) protein was observed starting at 50 μM SFN. Since XPA is absolutely required for nucleotide excision repair, the impact of SFN on the repair of (+)-anti-benzo[a]pyrene 7,8-diol-9,10-epoxide ((+)-anti-BPDE)-induced DNA adducts in HCT 116 cells was investigated. While preincubation with SFN did not affect initial lesion levels, a dose-dependent repair inhibition of (+)-anti-BPDE-induced DNA damage during the first 12 h after lesion induction was observed, starting at 1 μM SFN. In contrast, the later phase of DNA repair was not impaired by SFN. In support of an inactivation of XPA also in cells, SFN increased the (+)-anti-BPDE-induced cytotoxicity XPA dependently in XP12RO cells. Comparison of p53-proficient and p53-deficient cells revealed no difference in SFN-induced DNA repair inhibition, indicating that p53 is no cellular target of SFN. Since DNA repair processes are required to maintain DNA integrity, the presented data suggest a potential impairment of genomic stability by SFN.
authors.affiliation: Department of Food Chemistry and Toxicology, Institute of Applied Bioscience, Karlsruhe Institute of Technology (KIT), Adenauerring 20a, 76131, Karlsruhe, Germany.
authors.forename: Ann Liza
authors.initials: AL
authors.lastname: Piberger
authors.forename: Beate
authors.initials: B
authors.lastname: Köberle
authors.forename: Andrea
authors.initials: A
authors.lastname: Hartwig
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001937:Brassica / Q000737:chemistry*; D002460:Cell Line / Q000187:drug effects; D018736:DNA Adducts; D004260:DNA Repair / Q000187:drug effects*; D016158:Genes, p53; D045325:HCT116 Cells / Q000187:drug effects; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D013454:Sulfoxides; D051760:Xeroderma Pigmentosum Group A Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D018736:DNA Adducts; D017879:Isothiocyanates; D013454:Sulfoxides; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C016766:sulforaphane; D015032:Zinc