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000128387 0247_ $$2doi$$a10.1093/mutage/geu004
000128387 0247_ $$2pmid$$apmid:24598128
000128387 0247_ $$2ISSN$$a0267-8357
000128387 0247_ $$2ISSN$$a1464-3804
000128387 037__ $$aDKFZ-2017-04404
000128387 041__ $$aeng
000128387 082__ $$a570
000128387 1001_ $$aStiborová, Marie$$b0
000128387 245__ $$aThe influence of dicoumarol on the bioactivation of the carcinogen aristolochic acid I in rats.
000128387 260__ $$aOxford$$bOxford Univ. Press$$c2014
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000128387 520__ $$aAristolochic 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.
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000128387 650_7 $$2NLM Chemicals$$aAristolochic Acids
000128387 650_7 $$2NLM Chemicals$$aCarcinogens
000128387 650_7 $$2NLM Chemicals$$aCytochromes
000128387 650_7 $$2NLM Chemicals$$aDNA Adducts
000128387 650_7 $$2NLM Chemicals$$aMutagens
000128387 650_7 $$07QID3E7BG7$$2NLM Chemicals$$aDicumarol
000128387 650_7 $$094218WFP5T$$2NLM Chemicals$$aaristolochic acid I
000128387 650_7 $$0EC 1.14.14.1$$2NLM Chemicals$$aCyp1a2 protein, rat
000128387 650_7 $$0EC 1.14.14.1$$2NLM Chemicals$$aCytochrome P-450 CYP1A1
000128387 650_7 $$0EC 1.14.14.1$$2NLM Chemicals$$aCytochrome P-450 CYP1A2
000128387 650_7 $$0EC 1.6.5.2$$2NLM Chemicals$$aNAD(P)H Dehydrogenase (Quinone)
000128387 650_7 $$0EC 1.6.5.2$$2NLM Chemicals$$aNQO1 protein, rat
000128387 7001_ $$aLevová, Kateřina$$b1
000128387 7001_ $$aBárta, František$$b2
000128387 7001_ $$aŠulc, Miroslav$$b3
000128387 7001_ $$0P:(DE-HGF)0$$aFrei, Eva$$b4
000128387 7001_ $$aArlt, Volker M$$b5
000128387 7001_ $$0P:(DE-He78)5e6f79f3c71682d052bc2536749ca077$$aSchmeiser, Heinz$$b6$$eLast author$$udkfz
000128387 773__ $$0PERI:(DE-600)1497468-x$$a10.1093/mutage/geu004$$gVol. 29, no. 3, p. 189 - 200$$n3$$p189 - 200$$tMutagenesis$$v29$$x1464-3804$$y2014
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