Home > Publications database > The influence of dicoumarol on the bioactivation of the carcinogen aristolochic acid I in rats. > print

001     128387
005     20240228135055.0
024 7 _ |a 10.1093/mutage/geu004
|2 doi
024 7 _ |a pmid:24598128
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024 7 _ |a 0267-8357
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024 7 _ |a 1464-3804
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037 _ _ |a DKFZ-2017-04404
041 _ _ |a eng
082 _ _ |a 570
100 1 _ |a Stiborová, Marie
|b 0
245 _ _ |a The influence of dicoumarol on the bioactivation of the carcinogen aristolochic acid I in rats.
260 _ _ |a Oxford
|c 2014
|b Oxford Univ. Press
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
536 _ _ |a 315 - Imaging and radiooncology (POF3-315)
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588 _ _ |a Dataset connected to CrossRef, PubMed,
650 _ 7 |a Aristolochic Acids
|2 NLM Chemicals
650 _ 7 |a Carcinogens
|2 NLM Chemicals
650 _ 7 |a Cytochromes
|2 NLM Chemicals
650 _ 7 |a DNA Adducts
|2 NLM Chemicals
650 _ 7 |a Mutagens
|2 NLM Chemicals
650 _ 7 |a Dicumarol
|0 7QID3E7BG7
|2 NLM Chemicals
650 _ 7 |a aristolochic acid I
|0 94218WFP5T
|2 NLM Chemicals
650 _ 7 |a Cyp1a2 protein, rat
|0 EC 1.14.14.1
|2 NLM Chemicals
650 _ 7 |a Cytochrome P-450 CYP1A1
|0 EC 1.14.14.1
|2 NLM Chemicals
650 _ 7 |a Cytochrome P-450 CYP1A2
|0 EC 1.14.14.1
|2 NLM Chemicals
650 _ 7 |a NAD(P)H Dehydrogenase (Quinone)
|0 EC 1.6.5.2
|2 NLM Chemicals
650 _ 7 |a NQO1 protein, rat
|0 EC 1.6.5.2
|2 NLM Chemicals
700 1 _ |a Levová, Kateřina
|b 1
700 1 _ |a Bárta, František
|b 2
700 1 _ |a Šulc, Miroslav
|b 3
700 1 _ |a Frei, Eva
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700 1 _ |a Arlt, Volker M
|b 5
700 1 _ |a Schmeiser, Heinz
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|e Last author
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773 _ _ |a 10.1093/mutage/geu004
|g Vol. 29, no. 3, p. 189 - 200
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|t Mutagenesis
|v 29
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