RT Journal Article
SR Electronic
T1 Humanized Thymidine Kinase–NOG Mice Can Be Used to Identify Drugs That Cause Animal-Specific Hepatotoxicity: A Case Study with Furosemide
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 73
OP 78
DO 10.1124/jpet.115.224493
VO 354
IS 1
A1 Xu, Dan
A1 Michie, Sara A.
A1 Zheng, Ming
A1 Takeda, Saori
A1 Wu, Manhong
A1 Peltz, Gary
YR 2015
UL http://jpet.aspetjournals.org/content/354/1/73.abstract
AB Interspecies differences have limited the predictive utility of toxicology studies performed using animal species. A drug that could be a safe and effective treatment in humans could cause toxicity in animals, preventing it from being used in humans. We investigated whether the use of thymidine kinase (TK)–NOG mice with humanized livers could prevent this unfortunate outcome (i.e., “rescue” a drug for use in humans). A high dose of furosemide is known to cause severe liver toxicity in mice, but it is a safe and effective treatment in humans. We demonstrate that administration of a high dose of furosemide (200 mg/kg i.p.) causes extensive hepatotoxicity in control mice but not in humanized TK-NOG mice. This interspecies difference results from a higher rate of production of the toxicity-causing metabolite by mouse liver. Comparison of their survival curves indicated that the humanized mice were more resistant than control mice to the hepatotoxicity caused by high doses of furosemide. In this test case, humanized TK-NOG mouse studies indicate that humans could be safely treated with a high dose of furosemide.