title: Loss of VHL in RCC Reduces Repair and Alters Cellular Response to Benzo[a]pyrene.
abstract: Mutations of the von Hippel-Lindau (VHL) tumor suppressor gene occur in the majority of sporadic renal-cell carcinomas (RCC). Loss of VHL function is associated with stabilization of hypoxia-inducible factor α (HIFα). We and others demonstrated that there is a two-way interaction between the aryl hydrocarbon receptor, which is an important mediator in the metabolic activation and detoxification of carcinogens, and the HIF1-pathway leading to an increased genetic instability when both pathways are simultaneously activated. The aim of this study was to investigate how environmental carcinogens, such as benzo[a]pyrene (BaP), which can be metabolically activated to BaP-7,8-diOH-9,10-epoxide (BPDE) play a role in the etiology of RCC. We exposed VHL-deficient RCC4 cells, in which HIFα is stabilized regardless of oxygen tension, to 0.1 μM BaP for 18 h. The mutagenic BPDE-DNA adduct levels were increased in HIFα stabilized cells. Using qRT-PCR, we demonstrated that absence of VHL significantly induced the mRNA levels of AhR downstream target CYP1A1. Furthermore, HPLC analysis indicated that loss of VHL increased the concentration of BaP-7,8-dihydroxydiol, the pre-cursor metabolite of BPDE. Interestingly, the capacity to repair BPDE-DNA adducts in the HIFα stabilized RCC4 cells, was markedly reduced. Taken together, these data indicate that loss of VHL affects BaP-mediated genotoxic responses in RCC and decreases repair capacity.
authors.affiliation: Department of Toxicology, Maastricht University Medical Centre, NUTRIM-School for Nutrition, Toxicology and Metabolism, Maastricht University , Maastricht , Netherlands.
authors.forename: Marten A
authors.initials: MA
authors.lastname: Schults
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Oligschlaeger
authors.forename: Roger W
authors.initials: RW
authors.lastname: Godschalk
authors.forename: Frederik-Jan
authors.initials: FJ
authors.lastname: Van Schooten
authors.forename: Roland K
authors.initials: RK
authors.lastname: Chiu
keywords: carcinogens; metabolism; nucleotide excision repair; renal-cell carcinoma; von Hippel-Lindau