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Using cytochrome P-450 gene knock-out mice to study chemical metabolism, toxicity, and carcinogenicity
B I Ghanayem1, H Wang, S Sumner
1Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. Ghanayem@niehs.nih.gov
Abstract:
Cytochrome P-450 (CYP) enzymes are heme-containing proteins that carry out oxidative metabolism of a wide range of structurally diverse exogenous chemicals and therapeutic agents as well as endogenous compounds. For some of these xenobiotics, oxidative metabolism results in the formation of toxic, mutagenic, or carcinogenic metabolites. In the past, the role of CYP enzymes in metabolism and chemical-induced toxicity was studied indirectly through use of specific antibodies or inducers and inhibitors of these enzymes. Progress in molecular biology and the ability to bioengineer animal models that do not express CYP1A2, CYP1A1, CYP1B1, CYP2E1, or both CYP1A2 and CYP2E1 isozymes has allowed for direct investigations of the in vivo role of these enzymes in the metabolism, toxicity, and carcinogenicity of xenobiotics. This article reviews research conducted to date that utilizes these genetically bioengineered mice in metabolism, toxicity, or carcinogenicity studies of chemicals. Some studies showed a positive correlation between in vivo results and in vitro predictions for the role of a specific CYP in chemical-induced effects, whereas other studies did not support in vitro predictions. Work reviewed herein demonstrates the importance of using animal models for investigating the role of specific CYP enzymes in metabolism and chemical-induced toxicity or carcinogenicity rather than relying solely on in vitro techniques. Eventually, studies of this nature will facilitate a more accurate assessment of human risks with regard to chemicals by helping us to understand the relationships between chemical metabolism, carcinogenicity, and polymorphisms in CYP enzymes.
Insights
Genetically engineered mice lacking specific Cytochrome P-450 (CYP) enzymes allow direct in vivo studies of chemical metabolism and toxicity. These models are crucial for understanding chemical risks and validating in vitro predictions.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Cytochrome P-450 (CYP) enzymes are critical for metabolizing diverse compounds, sometimes producing toxic byproducts.
- Historically, CYP roles in toxicity were inferred indirectly using inhibitors or inducers.
Purpose of the Study:
- To review research employing genetically engineered animal models to directly investigate the in vivo role of specific CYP enzymes.
- To assess the utility of these models in understanding xenobiotic metabolism, toxicity, and carcinogenicity.
Main Methods:
- Utilizing genetically bioengineered mice lacking specific CYP isozymes (e.g., CYP1A2, CYP1A1, CYP1B1, CYP2E1).
- Conducting in vivo studies on chemical metabolism, toxicity, and carcinogenicity using these knockout models.
Main Results:
- Some studies using engineered mice showed good correlation between in vivo findings and in vitro predictions.
- Other studies revealed discrepancies between in vitro predictions and in vivo outcomes for specific CYP roles.
- Demonstrated the necessity of in vivo validation for understanding CYP-mediated chemical effects.
Conclusions:
- Genetically engineered animal models provide direct insights into the in vivo functions of CYP enzymes in chemical metabolism and toxicity.
- Reliance solely on in vitro methods may not accurately predict in vivo outcomes; animal models are essential.
- This research aids in more accurate human risk assessment by clarifying CYP-mediated chemical metabolism, carcinogenicity, and the impact of genetic polymorphisms.