The effect of aristolochic acid I on expression of NAD(P)H:quinone oxidoreductase in mice and rats--a comparative study
Language English Country Netherlands Media print-electronic
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
Grant support
14329
Cancer Research UK - United Kingdom
PubMed
24769487
DOI
10.1016/j.mrgentox.2014.01.012
PII: S1383-5718(14)00104-1
Knihovny.cz E-resources
- Keywords
- Aristolochic acid nephropathy, DNA adducts, Metabolic activation, NAD(P):quinone oxidoreductase, Protein expression,
- MeSH
- Enzyme Activation drug effects MeSH
- Cytosol enzymology MeSH
- Liver enzymology pathology MeSH
- Carcinogens pharmacology MeSH
- Rats MeSH
- Aristolochic Acids pharmacology MeSH
- Kidney enzymology pathology MeSH
- Mice, Knockout MeSH
- Mice MeSH
- NAD(P)H Dehydrogenase (Quinone) metabolism MeSH
- Lung enzymology pathology MeSH
- Rats, Wistar MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Names of Substances
- aristolochic acid I MeSH Browser
- Carcinogens MeSH
- Aristolochic Acids MeSH
- NAD(P)H Dehydrogenase (Quinone) MeSH
- Nqo1 protein, mouse MeSH Browser
- NQO1 protein, rat MeSH Browser
UNLABELLED: Aristolochic acid is the cause of aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN) and their associated urothelial malignancies. Using Western blotting, we investigated the expression of NAD(P)H: quinone oxidoreductase (NQO1), the most efficient cytosolic enzyme that reductively activates aristolochic acid I (AAI) in mice and rats. In addition, the effect of AAI on the expression of the NQO1 protein and its enzymatic activity in these experimental animal models was examined. We found that NQO1 protein levels in cytosolic fractions isolated from liver, kidney and lung of mice differed from those expressed in these organs of rats. In mice, the highest levels of NQO1 protein and NQO1 activity were found in the kidney, followed by lung and liver. In contrast, the NQO1 protein levels and enzyme activity were lowest in rat-kidney cytosol, whereas the highest amounts of NQO1 protein and activity were found in lung cytosols, followed by those of liver. NQO1 protein and enzyme activity were induced in liver and kidney of AAI-pretreated mice compared with those of untreated mice. NQO1 protein and enzyme activity were also induced in rat kidney by AAI. Furthermore, the increase in hepatic and renal NQO1 enzyme activity was associated with AAI bio-activation and elevated AAI-DNA adduct levels were found in ex vivo incubations of cytosolic fractions with DNA and AAI. In conclusion, our results indicate that AAI can 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
