Knockout and humanized mice as suitable tools to identify enzymes metabolizing the human carcinogen aristolochic acid
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't, Review
Grant support
14329
Cancer Research UK - United Kingdom
- MeSH
- DNA Adducts metabolism MeSH
- Cytochrome P-450 CYP1A1 genetics metabolism MeSH
- Cytochrome P-450 CYP1A2 genetics metabolism MeSH
- Enzymes genetics metabolism MeSH
- Enzyme Inhibitors pharmacology MeSH
- Carcinogens metabolism pharmacokinetics MeSH
- Aristolochic Acids metabolism pharmacokinetics toxicity MeSH
- Humans MeSH
- Inactivation, Metabolic * MeSH
- Mice, Knockout * MeSH
- Mice MeSH
- NAD(P)H Dehydrogenase (Quinone) antagonists & inhibitors MeSH
- NADPH-Ferrihemoprotein Reductase genetics metabolism MeSH
- Kidney Diseases chemically induced MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Names of Substances
- DNA Adducts MeSH
- aristolochic acid I MeSH Browser
- CYP1A1 protein, human MeSH Browser
- CYP1A2 protein, human MeSH Browser
- Cytochrome P-450 CYP1A1 MeSH
- Cytochrome P-450 CYP1A2 MeSH
- Enzymes MeSH
- Enzyme Inhibitors MeSH
- Carcinogens MeSH
- Aristolochic Acids MeSH
- NAD(P)H Dehydrogenase (Quinone) MeSH
- NADPH-Ferrihemoprotein Reductase MeSH
- NQO1 protein, human MeSH Browser
UNLABELLED: 1. Aristolochic acid I (AAI) is the predominant component in plant extract of Aristolochia genus that is involved in development of aristolochic acid nephropathy, Balkan endemic nephropathy and urothelial cancer. The diseases do not develop in all individuals exposed to AAI and patients exhibit different clinical outcomes. Differences in the activities of enzymes catalyzing the metabolism of AAI might be one of the reasons for this individual susceptibility. 2. Understanding which human enzymes are involved in reductive activation of AAI generating AAI-DNA adducts, and/or its detoxication to the O-demethylated metabolite, aristolochic acid Ia (AAIa), is necessary in the assessment of the susceptibility to this compound. 3. This review summarizes the results of the latest studies utilizing genetically engineered mouse models to identify which human and rodent enzymes catalyze the reductive activation of AAI to AAI-DNA adducts and its oxidative detoxication to AAIa in vivo. 4. The use of hepatic cytochrome P450 (Cyp) reductase null (HRN) mice, in which NADPH:Cyp oxidoreductase (Por) is deleted in hepatocytes, Cyp1a1((-/-)), Cyp1a2((-/-)) single-knockout, Cyp1a1/1a2((-/-)) double-knockout and CYP1A-humanized mice revealed that mouse and human CYP1A1 and 1A2, besides mouse NAD(P)H: quinone oxidoreductase, were involved in the activation of AAI but CYP1A1 and 1A2 also oxidatively detoxified AAI.
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
