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
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
14329
Cancer Research UK - United Kingdom
R01 ES ES014403
NIEHS NIH HHS - United States
P30 ES006096
NIEHS NIH HHS - United States
PubMed
22982977
DOI
10.1016/j.taap.2012.09.004
PII: S0041-008X(12)00400-0
Knihovny.cz E-zdroje
- MeSH
- adukty DNA metabolismus MeSH
- balkánská nefropatie enzymologie genetika metabolismus MeSH
- buněčné linie MeSH
- cytochrom P-450 CYP1A1 nedostatek genetika metabolismus MeSH
- cytochrom P-450 CYP1A2 nedostatek genetika metabolismus MeSH
- cytosol enzymologie metabolismus MeSH
- játra účinky léků enzymologie metabolismus MeSH
- kyseliny aristolochové farmakokinetika toxicita MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši transgenní MeSH
- myši MeSH
- NAD(P)H dehydrogenasa (chinon) biosyntéza metabolismus MeSH
- western blotting MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- adukty DNA MeSH
- aristolochic acid I MeSH Prohlížeč
- cytochrom P-450 CYP1A1 MeSH
- cytochrom P-450 CYP1A2 MeSH
- kyseliny aristolochové MeSH
- NAD(P)H dehydrogenasa (chinon) MeSH
Aristolochic 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.
Citace poskytuje Crossref.org
The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro
Balkan endemic nephropathy: an update on its aetiology
