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Animal Model with “Humanized” Liver Predicts Drug Toxicity in Human Livers

Scientists have enlisted a special type of mouse with human cells in its liver for a proof of concept study to predict which experimental drugs can cause liver failure and should thus not be tested in humans. As the primary spot for drug metabolism, the liver is particularly susceptible to injury from some drugs, which can result in liver failure, need for a transplant, and death. Animals such as mice are often used to test experimental drugs for any dangerous side effects before these drugs are tested in clinical trials. However, these animal models feature key physiological differences from humans that can cause a drug to be benign in the animals, yet harmful in humans. For example, in 1993, a clinical trial of a drug called fialuridine resulted in liver failure in 7 of the 15 participants, despite no indications the drug could cause liver problems when tested earlier in multiple animal models. In the recent study, a group of scientists sought a better way to test drugs for liver toxicity in the laboratory. To do this, they used “chimeric” mice whose own liver cells were mostly replaced with liver cells from human donors. Both male and female mice, as well as liver cells from both female and male donors, were used. The scientists proceeded to determine whether they could detect signs of drug induced liver toxicity in the human, but not rodent, cells. Specifically, they tested whether this model could have been used to predict the human-specific liver failure caused by the drug fialuridine. After 4 days of treatment with the highest dose, the chimeric mice showed signs of liver toxicity, such as elevated liver enzymes, fatty liver, and cellular changes, while the control mice without any human cells did not. They then treated both the chimeric and control mice with another drug known not to cause liver failure in humans; the lack of toxic effects showed the model could distinguish drugs that cause human liver failure from those that do not. This study demonstrates the utility of this kind of animal model with a humanized liver for screening experimental drugs. Use of these pre-clinical animal models could reduce the chances of exposing volunteers in clinical trials to experimental drugs that can cause acute liver failure.


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