Researchers from MIT have found that genes involved in drug metabolism are regulated by circadian rhythms, affecting how drugs are metabolized in the liver. By using tiny, engineered livers derived from human cells, they found that enzymes responsible for breaking down drugs like Tylenol vary in abundance at different times of the day. This discovery could lead to the development of better dosing schedules for drugs to maximize efficacy and minimize toxicity.
Over 300 liver genes were identified to follow circadian cycles, including those involved in drug metabolism and inflammation. Analyzing these rhythms could lead to improved drug regimens for existing medications. The study also revealed that the liver is more susceptible to infections such as malaria at certain points in the circadian cycle, when fewer inflammatory proteins are being produced. This information could help researchers better understand how infections take hold in the liver at specific times of the day.
Using miniaturized livers developed from human hepatocytes in the lab, the researchers were able to create synchronized circadian oscillations in the liver cells. They identified genes expressed in waves, including those related to drug metabolism, glucose and lipid metabolism, and immune processes. By studying the effects of circadian cycles on drug metabolism, researchers found that drug toxicity and efficacy could vary significantly depending on the time of day the drug is administered.
Most drugs are metabolized by enzymes following circadian cycles, which could impact their effectiveness and toxicity. By identifying the best times of the day to administer drugs, researchers hope to maximize their benefits while minimizing side effects. Collaborators are now investigating how cancer drugs and pain management medications are affected by circadian rhythms and how dosing schedules can be optimized for maximum effect.
In addition to drug metabolism, researchers found that immune response genes in the liver follow circadian cycles, affecting susceptibility to infections like malaria. By exposing engineered livers to the malaria parasite at different times of the circadian cycle, researchers found that infection rates varied depending on when the exposure took place. Understanding these variations could lead to better strategies for preventing and treating infections that target the liver.
This research opens up new possibilities for studying infections in the liver and how they are affected by circadian rhythms. By manipulating the timing of infections, researchers were able to increase infection rates in engineered livers, allowing for more effective drug screens. Funding for the study was provided by multiple sources, including MIT and research agencies in the US and France. Ultimately, studying circadian rhythms in drug metabolism and infection susceptibility could revolutionize how medications are administered and how infections are treated in the future.
