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Schults MA, Oligschlaeger Y, Godschalk RW, et al. Loss of VHL in RCC Reduces Repair and Alters Cellular Response to Benzo[a]pyrene. Front Oncol. 2013;3:270doi: 10.3389/fonc.2013.00270.
Schults, M. A., Oligschlaeger, Y., Godschalk, R. W., Van Schooten, F. J., & Chiu, R. K. (2013). Loss of VHL in RCC Reduces Repair and Alters Cellular Response to Benzo[a]pyrene. Frontiers in oncology, 3270. https://doi.org/10.3389/fonc.2013.00270
Schults, Marten A, et al. "Loss of VHL in RCC Reduces Repair and Alters Cellular Response to Benzo[a]pyrene." Frontiers in oncology vol. 3 (2013): 270. doi: https://doi.org/10.3389/fonc.2013.00270
Schults MA, Oligschlaeger Y, Godschalk RW, Van Schooten FJ, Chiu RK. Loss of VHL in RCC Reduces Repair and Alters Cellular Response to Benzo[a]pyrene. Front Oncol. 2013 Oct 28;3:270. doi: 10.3389/fonc.2013.00270. eCollection 2013. PMID: 24195061; PMCID: PMC3809518.
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Front Oncol. 2013 Oct 28;3:270. doi: 10.3389/fonc.2013.00270. eCollection 2013.

Loss of VHL in RCC Reduces Repair and Alters Cellular Response to Benzo[a]pyrene.

Frontiers in oncology

Marten A Schults, Yvonne Oligschlaeger, Roger W Godschalk, Frederik-Jan Van Schooten, Roland K Chiu

Affiliations

  1. Department of Toxicology, Maastricht University Medical Centre, NUTRIM-School for Nutrition, Toxicology and Metabolism, Maastricht University , Maastricht , Netherlands.

PMID: 24195061 PMCID: PMC3809518 DOI: 10.3389/fonc.2013.00270

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.

Keywords: carcinogens; metabolism; nucleotide excision repair; renal-cell carcinoma; von Hippel-Lindau

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