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@ARTICLE{Brta:177024,
      author       = {F. Bárta and A. Dedíková and M. Bebová and Š.
                      Dušková and J. Mráz and H. Schmeiser$^*$ and V. M. Arlt
                      and P. Hodek and M. Stiborová},
      title        = {{C}o-{E}xposure to {A}ristolochic {A}cids {I} and {II}
                      {I}ncreases {DNA} {A}dduct {F}ormation {R}esponsible for
                      {A}ristolochic {A}cid {I}-{M}ediated {C}arcinogenicity in
                      {R}ats.},
      journal      = {International journal of molecular sciences},
      volume       = {22},
      number       = {19},
      issn         = {1422-0067},
      address      = {Basel},
      publisher    = {Molecular Diversity Preservation International},
      reportid     = {DKFZ-2021-02254},
      pages        = {10479},
      year         = {2021},
      abstract     = {The plant extract aristolochic acid (AA), containing
                      aristolochic acids I (AAI) and II (AAII) as major
                      components, causes aristolochic acid nephropathy (AAN) and
                      Balkan endemic nephropathy (BEN), unique renal diseases
                      associated with upper urothelial cancer. Recently (Chemical
                      Research in Toxicology 33(11), 2804-2818, 2020), we showed
                      that the in vivo metabolism of AAI and AAII in Wistar rats
                      is influenced by their co-exposure (i.e., AAI/AAII mixture).
                      Using the same rat model, we investigated how exposure to
                      the AAI/AAII mixture can influence AAI and AAII DNA adduct
                      formation (i.e., AA-mediated genotoxicity). Using
                      32P-postlabelling, we found that AA-DNA adduct formation was
                      increased in the livers and kidneys of rats treated with
                      AAI/AAII mixture compared to rats treated with AAI or AAII
                      alone. Measuring the activity of enzymes involved in AA
                      metabolism, we showed that enhanced AA-DNA adduct formation
                      might be caused partially by both decreased AAI
                      detoxification as a result of hepatic CYP2C11 inhibition
                      during treatment with AAI/AAII mixture and by hepatic or
                      renal NQO1 induction, the key enzyme predominantly
                      activating AA to DNA adducts. Moreover, our results indicate
                      that AAII might act as an inhibitor of AAI detoxification in
                      vivo. Consequently, higher amounts of AAI might remain in
                      liver and kidney tissues, which can be reductively
                      activated, resulting in enhanced AAI DNA adduct formation.
                      Collectively, these results indicate that AAII present in
                      the plant extract AA enhances the genotoxic properties of
                      AAI (i.e., AAI DNA adduct formation). As patients suffering
                      from AAN and BEN are always exposed to the plant extract
                      (i.e., AAI/AAII mixture), our findings are crucial to better
                      understanding host factors critical for AAN- and
                      BEN-associated urothelial malignancy.},
      keywords     = {Balkan endemic nephropathy (Other) / DNA adducts (Other) /
                      NAD(P)H:quinone oxidoreductase 1 (Other) / aristolochic acid
                      I (Other) / aristolochic acid II (Other) / aristolochic acid
                      nephropathy (Other) / aristolochic acid-mediated
                      carcinogenesis (Other) / cytochrome P450 (Other) /
                      genotoxicity (Other)},
      cin          = {E030},
      ddc          = {540},
      cid          = {I:(DE-He78)E030-20160331},
      pnm          = {315 - Bildgebung und Radioonkologie (POF4-315)},
      pid          = {G:(DE-HGF)POF4-315},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34638820},
      doi          = {10.3390/ijms221910479},
      url          = {https://inrepo02.dkfz.de/record/177024},
}