Humans express several proteins that breakdown the synthetic chemicals and drugs (collectively known as xenobiotics) that we ingest or are administered. Expression of these proteins is itself regulated by the xenobiotic-sensing proteins PXR and CAR. Developing animal models to determine the relative importance of PXR and CAR for humans to breakdown a specific drug has been difficult because the human and animal proteins sense different xenobiotics.
However, Nico Scheer and colleagues, at TaconicArtemis, Germany, have now developed a panel of mice that will help researchers address this issue and enable them to predict more accurately how drugs are likely to be broken down in humans, providing important information regarding probable toxicity and efficacy. The researchers report their findings in the Aug. 1 issue of the Journal of Clinical Investigation.
In the study, four types of mouse were generated: mice that lacked PXR, mice that lacked CAR, mice that expressed human PXR in place of mouse PXR, and mice that expressed human CAR in place of mouse CAR. In addition, breeding these different mice in various combinations led to the generation of mice expressing both human PXR and human CAR and mice lacking both PXR and CAR.
To prove that this panel of mice could be used to more effectively evaluate how PXR and CAR are likely to influence drug breakdown, they were used to demonstrate that upregulation of drug-destroying enzymes by the barbiturate Phenobarbital is mediated by only CAR, whereas previous in vitro studies had indicated a role for both PXR and CAR.
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