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Pharmaceutical use of mouse models humanized for the xenobiotic receptor
1Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Abstract:
The regulation of hepatic cytochrome P450 (CYP) enzymes is implicated in both drug metabolism and drug-drug interactions. The CYP genes are induced by numerous xenobiotics, yet the inducibility shows clear species specificity. Recently, the rodent nuclear receptor PXR and its human homolog, SXR or hPXR, have been established as species-specific xeno-sensors that regulate CYP3A enzymes. By knocking-out the rodent gene and replacing it with the human receptor, a 'humanized' mouse model has been established. Displaying a human drug-response profile, this mouse represents a unique tool to dissect the drug-induced xenobiotic response and should aid the development of safer drugs.
Insights
Researchers developed a humanized mouse model to study drug metabolism. This model mimics human responses, aiding in the development of safer drugs by understanding xenobiotic interactions with cytochrome P450 enzymes.
Area of Science:
- Pharmacology
- Drug Metabolism
- Toxicology
Background:
- Hepatic cytochrome P450 (CYP) enzymes are crucial for drug metabolism and can cause drug-drug interactions.
- Xenobiotics induce CYP genes, but this induction is species-specific.
- The nuclear receptors PXR (rodent) and SXR/hPXR (human) act as species-specific sensors regulating CYP3A enzymes.
Purpose of the Study:
- To establish a 'humanized' mouse model for studying species-specific xenobiotic responses.
- To investigate the role of human SXR/hPXR in regulating drug metabolism.
- To provide a tool for dissecting drug-induced xenobiotic responses and improving drug safety.
Main Methods:
- Gene knockout of the rodent PXR receptor.
- Gene replacement with the human SXR/hPXR receptor to create a 'humanized' mouse model.
- Analysis of drug response profiles in the humanized mouse model.
Main Results:
- The 'humanized' mouse model successfully mimics human drug-response profiles.
- This model demonstrates species-specific xenobiotic sensing via hPXR.
- The model is effective in studying drug-induced regulation of CYP3A enzymes.
Conclusions:
- The humanized mouse model is a valuable tool for understanding human drug metabolism and drug-drug interactions.
- This model facilitates the dissection of xenobiotic responses mediated by hPXR.
- It is expected to contribute to the development of safer pharmaceutical agents.