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Knockout and humanized mice as suitable tools to identify enzymes metabolizing the human carcinogen aristolochic acid
Marie Stiborová1, Eva Frei, Volker M Arlt
1Department of Biochemistry, Faculty of Science, Charles University , Prague , Czech Republic .
Abstract:
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.
Insights
Enzymes like CYP1A1 and CYP1A2 are involved in activating aristolochic acid I (AAI) and detoxifying it. Understanding these enzyme activities helps assess individual susceptibility to AAI-induced diseases.
Area of Science:
- Toxicology
- Pharmacology
- Genetics
Background:
- Aristolochic acid I (AAI) causes nephropathy and urothelial cancer, but individual susceptibility varies.
- Enzyme metabolism differences may explain varying clinical outcomes and disease development after AAI exposure.
Purpose of the Study:
- Identify human and rodent enzymes responsible for AAI's reductive activation and oxidative detoxification.
- Assess the role of specific enzymes in generating AAI-DNA adducts and detoxifying AAI to AAIa.
Main Methods:
- Utilized genetically engineered mouse models, including hepatic cytochrome P450 (Cyp) reductase null (HRN) mice, Cyp1a1/1a2 single and double knockouts, and CYP1A-humanized mice.
- Investigated the in vivo catalytic activities of mouse and human enzymes in AAI metabolism.
Main Results:
- Mouse and human CYP1A1 and CYP1A2 were identified as key enzymes in both the reductive activation and oxidative detoxification of AAI.
- NAD(P)H:quinone oxidoreductase was also implicated in AAI activation.
Conclusions:
- CYP1A1 and CYP1A2 play a dual role in AAI metabolism, contributing to both its activation and detoxification.
- Further research into these enzymes is crucial for understanding and mitigating AAI-induced toxicity.
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