Before any new drug hits the market it can undergo years of testing for effectiveness and safety. However, many do not make it past this point because lab models cannot accurately predict how a human will eventually metabolize the drug. Now, researchers at Baylor College of Medicine have developed a new mouse model with human cells that closer resembles the human liver – the primary organ of drug metabolism.
The findings, which show more accurate results as to how a human might metabolize a drug, are found in the latest edition of Nature Communications.
“We have been improving upon these type of mouse models since the early 2000s. From the start researchers could replicate human specific viruses such as hepatitis B and C virus but there were still challenges for drug testing,” said Karl-Dimiter Bissig, assistant professor in the Center for Stem Cells and Regenerative Medicine at Baylor. “The problem was that the remaining murine liver tissue created mouse specific modifications of the drug, which made it virtually impossible to predict human drug metabolism.”
The many P450 cytochromes are the main drug metabolizing enzymes in the body. However, mice like all other laboratory animals have a completely different set of cytochromes than humans, which makes it difficult to draw concussions for humans when testing drugs in mice.
“We decided to functionally inhibit those enzymes in the murine part of the liver,” Bissig said. “Since there is only one electron donor to all murine cytochromes, the P450 oxidoreductase, we delete that gene. If the cytochromes don’t get the electron, they are no longer functional and only the human cells in the liver can metabolize the drugs.”
To test this new model Bissig and his team used a cancer drug and an antiviral drug. The models showed more accurately when it comes to the process of how a human metabolizes the drugs.
“Is this the perfect model? Not yet, more testing, modifications and improvements are needed, but this is definitely the next generation of mouse models,” Bissig said. “Our finding prove that there is great promise that we can help patients avoid harmful side effects by more accurately testing drugs before use in humans.”
While this new model focuses on liver cells, Bissig says there is a possibility for this model to study toxicity also in other organs.
“Toxicity is mainly metabolite driven, and the liver is the main organ to generate those metabolites. More studies and work are needed but we think that this model can also be used to study drug toxicity in addition to metabolism.”
Other’s who contributed to this study include lead author Mercedes Barzi, Francis P. Pankowicz, Barry Zorman, Xing Liu, Xavier Legras, Diane Yang, Malgorzata Borowiak (McNair Scholar), Beatrice Bissig-Choisat, Pavel Sumazin, and Feng Li, all with Baylor College of Medicine.
Funding for this study comes from: The National Heart Lung and Blood Institute (R01HL134510), the Texas Hepatocellular Carcinoma Consortium, CPRIT (#RP150587), the Diana Helis Henry and Adrienne Helis Malvin Medical Research Foundations, T32HL092332, P30CA125123, CMM core facility of Texas Medical Center Digestive Disease Center (P30-DK56338), NCI Cancer Center Support Grant (P30CA125123).