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@ARTICLE{Stiborov:128387,
      author       = {M. Stiborová and K. Levová and F. Bárta and M. Šulc and
                      E. Frei$^*$ and V. M. Arlt and H. Schmeiser$^*$},
      title        = {{T}he influence of dicoumarol on the bioactivation of the
                      carcinogen aristolochic acid {I} in rats.},
      journal      = {Mutagenesis},
      volume       = {29},
      number       = {3},
      issn         = {1464-3804},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2017-04404},
      pages        = {189 - 200},
      year         = {2014},
      abstract     = {Aristolochic acid I (AAI) is the major toxic component of
                      the plant extract AA, which leads to the development of
                      nephropathy and urothelial cancer in human. Individual
                      susceptibility to AAI-induced disease might reflect
                      variability in enzymes that metabolise AAI. In vitroquinone
                      oxidoreductase (NQO1) is the most potent enzyme that
                      activates AAI by catalyzing formation of AAI-DNA adducts,
                      which are found in kidneys of patients exposed to AAI.
                      Inhibition of renal NQO1 activity by dicoumarol has been
                      shown in mice. Here, we studied the influence of dicoumarol
                      on metabolic activation of AAI in Wistar rats in vivo. In
                      contrast to previous in vitro findings, dicoumarol did not
                      inhibit AAI-DNA adduct formation in rats. Compared with rats
                      treated with AAI alone, 11- and 5.4-fold higher AAI-DNA
                      adduct levels were detected in liver and kidney,
                      respectively, of rats pretreated with dicoumarol prior to
                      exposure to AAI. Cytosols and microsomes isolated from liver
                      and kidney of these rats were analysed for activity and
                      protein levels of enzymes known to be involved in AAI
                      metabolism. The combination of dicoumarol with AAI induced
                      NQO1 protein level and activity in both organs. This was
                      paralleled by an increase in AAI-DNA adduct levels found in
                      ex vivo incubations with cytosols from rats pretreated with
                      dicoumarol compared to cytosols from untreated rats.
                      Microsomal ex vivo incubations showed a lower AAI
                      detoxication to its oxidative metabolite,
                      8-hydroxyaristolochic acid (AAIa), although cytochrome P450
                      (CYP) 1A was practically unchanged. Because of these
                      unexpected results, we examined CYP2C activity in microsomes
                      and found that treatment of rats with dicoumarol alone and
                      in combination with AAI inhibited CYP2C6/11 in liver.
                      Therefore, these results indicate that CYP2C enzymes might
                      contribute to AAI detoxication.},
      keywords     = {Aristolochic Acids (NLM Chemicals) / Carcinogens (NLM
                      Chemicals) / Cytochromes (NLM Chemicals) / DNA Adducts (NLM
                      Chemicals) / Mutagens (NLM Chemicals) / Dicumarol (NLM
                      Chemicals) / aristolochic acid I (NLM Chemicals) / Cyp1a2
                      protein, rat (NLM Chemicals) / Cytochrome P-450 CYP1A1 (NLM
                      Chemicals) / Cytochrome P-450 CYP1A2 (NLM Chemicals) /
                      NAD(P)H Dehydrogenase (Quinone) (NLM Chemicals) / NQO1
                      protein, rat (NLM Chemicals)},
      cin          = {G110 / C016 / E030},
      ddc          = {570},
      cid          = {I:(DE-He78)G110-20160331 / I:(DE-He78)C016-20160331 /
                      I:(DE-He78)E030-20160331},
      pnm          = {315 - Imaging and radiooncology (POF3-315)},
      pid          = {G:(DE-HGF)POF3-315},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:24598128},
      doi          = {10.1093/mutage/geu004},
      url          = {https://inrepo02.dkfz.de/record/128387},
}