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
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
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-resources
- MeSH
- DNA Adducts metabolism MeSH
- Balkan Nephropathy enzymology genetics metabolism MeSH
- Cell Line MeSH
- Cytochrome P-450 CYP1A1 deficiency genetics metabolism MeSH
- Cytochrome P-450 CYP1A2 deficiency genetics metabolism MeSH
- Cytosol enzymology metabolism MeSH
- Liver drug effects enzymology metabolism MeSH
- Aristolochic Acids pharmacokinetics toxicity MeSH
- Humans MeSH
- Mice, Inbred C57BL MeSH
- Mice, Knockout MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- NAD(P)H Dehydrogenase (Quinone) biosynthesis metabolism MeSH
- Blotting, Western MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- DNA Adducts MeSH
- aristolochic acid I MeSH Browser
- Cytochrome P-450 CYP1A1 MeSH
- Cytochrome P-450 CYP1A2 MeSH
- Aristolochic Acids MeSH
- NAD(P)H Dehydrogenase (Quinone) 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.
References provided by 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
