title: Dicoumarol inhibits rat NAD(P)H:quinone oxidoreductase in vitro and induces its expression in vivo.
abstract: OBJECTIVE
  Dicoumarol is known to act as an inhibitor of
  quinone oxidoreductase (NQO1). This cytosolic reductase significantly contributes to the genotoxicity of the nephrotoxic and carcinogenic alkaloid aristolochic acid I (AAI). Aristolochic acid causes aristolochic acid nephropathy (AAN), and Balkan endemic nephropathy (BEN), as well as associated urothelial malignancies. NQO1 is the most efficient enzyme responsible for the reductive bioactivation of AAI to species forming covalent AAI-DNA adducts. However, it is still not known how dicoumarol influences the NQO1-mediated reductive bioactivation of AAI.
  
  
  METHODS
  AAI-DNA adduct formation was determined by 32P-postlabeling. Expression of NQO1 mRNA and NQO1 protein was determined by real-time polymerase chain reaction and Western blotting, respectively.
  
  
  RESULTS
  In this study, dicoumarol inhibited AAI bioactivation to form AAI-DNA adducts mediated by rat and human NQO1 in vitro as expected. We however, demonstrated that dicoumarol acts as an inducer of NQO1 in kidney and lung of rats treated with this NQO1 inhibitor in vivo, both at protein and activity levels. This NQO1 induction increased the potency of kidney cytosol to bioactivate AAI and elevated AAI-DNA adduct levels were found in ex-vivo incubations of AAI with renal cytosols and DNA. NQO1 mRNA levels were induced in liver only by dicoumarol.
  
  
  CONCLUSIONS
  Our results indicate a dual role of dicoumarol in NQO1-mediated genotoxicty of AAI. It acts both as an NQO1 inhibitor mainly in vitro and as an NQO1 inducer if administered to rats.
authors: Marie
authors: M
authors: Stiborova
authors: Katerina
authors: K
authors: Levova
authors: Frantisek
authors: F
authors: Barta
authors: Helena
authors: H
authors: Dracinska
authors: Miroslav
authors: M
authors: Sulc
authors: Petr
authors: P
authors: Hodek
authors: Eva
authors: E
authors: Frei
authors: Volker M
authors: VM
authors: Arlt
authors: Heinz H
authors: HH
authors: Schmeiser
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000378:metabolism*; D001728:Dicumarol / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D011808:Quinone Reductases / Q000378:metabolism*; D051381:Rats
chemical_list: D034341:Aristolochic Acids; D004791:Enzyme Inhibitors; D001728:Dicumarol; C000228:aristolochic acid I; C087049:NADPH - phenanthrenequinone oxidoreductase; D011808:Quinone Reductases