NAD(P)H:quinone oxidoreductase expression in Cyp1a-knockout and CYP1A-humanized mouse lines and its effect on bioactivation of the carcinogen aristolochic acid I.
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Nebert, Daniel W.
Phillips, David H.
Schmeiser, Heinz H.
Arlt, Volker M.
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AbstractAristolochic acid causes a specific nephropathy (AAN), Balkan endemic nephropathy, and urothelial malignancies. Using Western blotting suitable to determine protein expression, we investigated in several transgenic mouse lines expression of NAD(P)H:quinone oxidoreductase (NQO1)-the most efficient cytosolic enzyme that reductively activates aristolochic acid I (AAI). The mouse tissues used were from previous studies [Arlt et al., Chem. Res. Toxicol. 24 (2011) 1710; Stiborova et al., Toxicol. Sci. 125 (2012) 345], in which the role of microsomal cytochrome P450 (CYP) enzymes in AAI metabolism in vivo had been determined. We found that NQO1 levels in liver, kidney and lung of Cyp1a1⁻/⁻, Cyp1a2⁻/⁻ and Cyp1a1/1a2⁻/⁻ knockout mouse lines, as well as in two CYP1A-humanized mouse lines harboring functional human CYP1A1 and CYP1A2 and lacking the mouse Cyp1a1/1a2 orthologs, differed from NQO1 levels in wild-type mice. NQO1 protein and enzymic activity were induced in hepatic and renal cytosolic fractions isolated from AAI-pretreated mice, compared with those in untreated mice. Furthermore, this increase in hepatic NQO1 enzyme activity was associated with bioactivation of AAI and elevated AAI-DNA adduct levels in ex vivo incubations of cytosolic fractions with DNA and AAI. In conclusion, AAI appears to increase its own metabolic activation by inducing NQO1, thereby enhancing its own genotoxic potential.
CitationToxicol. Appl. Pharmacol. 2012, 265 (3):360-367
SponsorsFinancial support from GACR (grant 303/09/0472 and 305/09/H008) and Charles University in Prague (UNCE 204025/2012) is highly acknowledged. Work at King's College London is supported by Cancer Research UK. D.H. Phillips and V.M. Arlt are members of the European Union Network of Excellence ECNIS2 (Environmental Cancer Risk, Nutrition and Individual Susceptibility). D.W. Nebert has been supported by R01 ES ES014403 and the P30 ES006096 Center grant.
- Role of P450 1A1 and P450 1A2 in bioactivation versus detoxication of the renal carcinogen aristolochic acid I: studies in Cyp1a1-/-, Cyp1a2-/-, and Cyp1a1/1a2-/- mice.
- Authors: Arlt VM, Levová K, Bárta F, Shi Z, Evans JD, Frei E, Schmeiser HH, Nebert DW, Phillips DH, Stiborová M
- Issue date: 2011 Oct 17
- Bioactivation versus detoxication of the urothelial carcinogen aristolochic acid I by human cytochrome P450 1A1 and 1A2.
- Authors: Stiborová M, Levová K, Bárta F, Shi Z, Frei E, Schmeiser HH, Nebert DW, Phillips DH, Arlt VM
- Issue date: 2012 Feb
- The effect of aristolochic acid I on expression of NAD(P)H:quinone oxidoreductase in mice and rats--a comparative study.
- Authors: Bárta F, Levová K, Frei E, Schmeiser HH, Arlt VM, Stiborová M
- Issue date: 2014 Jul 1
- Knockout and humanized mice as suitable tools to identify enzymes metabolizing the human carcinogen aristolochic acid.
- Authors: Stiborová M, Frei E, Arlt VM, Schmeiser HH
- Issue date: 2014 Jan
- Role of cytochromes P450 1A1/2 in detoxication and activation of carcinogenic aristolochic acid I: studies with the hepatic NADPH:cytochrome P450 reductase null (HRN) mouse model.
- Authors: Levová K, Moserová M, Kotrbová V, Sulc M, Henderson CJ, Wolf CR, Phillips DH, Frei E, Schmeiser HH, Mares J, Arlt VM, Stiborová M
- Issue date: 2011 May