Researchers have found that over 300 liver genes are regulated by the circadian rhythm. This rhythm can impact the availability of drugs and how effectively the body can metabolize them. A recent study from MIT suggests that administering drugs at different times of day could greatly influence their metabolism in the liver.
Using miniature, lab-grown livers made from human donor cells, the researchers observed that numerous genes responsible for drug metabolism are subject to circadian regulation. These variations can influence the availability of drugs and how efficiently the body can break them down.The process of drug metabolism in the body can be broken down, as evidenced by the discovery of enzymes that break down drugs like Tylenol being more abundant at certain times of the day. The study identified over 300 liver genes that operate on a circadian clock, many of which are involved in drug metabolism and other functions such as inflammation. By analyzing these rhythms, researchers could improve dosing schedules for current drugs. Sangeeta Bhatia, the John and Doro, suggests that this method could be used to optimize the efficacy and minimize the toxicity of already approved drugs.The author of the new study, which appears today in Science Advances, is Bhatia. She is a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science (IMES). The study also found that the liver is more vulnerable to infections like malaria at certain points in the circadian cycle, when fewer inflammatory proteins are produced. Sandra March, a research scientist in IMES, is the paper’s lead author. Thy Wilson Professor of Health Sciences and Technology, and Electrical Engineering and Computer Science at MIT discovered that metabolic cycles play a significant role.It is believed that around 50% of human genes operate on a circadian rhythm, and a large number of these genes are active in the liver. However, studying the impact of circadian rhythms on liver function has been challenging due to variations between the genes in mice and humans, making it impossible to use mouse models for research purposes.
Bhatia’s team has previously developed a method for growing miniature livers using human donor liver cells called hepatocytes. In this research project, they aimed to determine whether these engineered livers possess their own circadian clocks.
They collaborated with Charl to conduct the study.Rice’s team at Rockefeller University discovered specific conditions that can promote the daily expression of a clock gene known as Bmal1. This particular gene is responsible for controlling the rhythmic expression of many other genes and allowed the liver cells to establish synchronized daily rhythms. The researchers then monitored the gene expression in these cells at three-hour intervals over a 48-hour period, leading to the identification of over 300 genes that exhibited rhythmic expression patterns.
The majority of these genes fell into two distinct groups – approximately 70% of the genes reached their peak expression levels at the same time, while the remaining 30% were at their lowest levels when the others were at their highest.The genes included in the study are involved in various functions such as drug metabolism, glucose and lipid metabolism, and different immune processes. The engineered livers were able to establish circadian cycles, allowing researchers to investigate how these cycles affect liver function. Specifically, the researchers looked at how the time of day would impact drug metabolism by studying acetaminophen (Tylenol) and atorvastatin, a drug used for treating high cholesterol. When Tylenol is broken down in the liver, a small portion of it is converted into a toxic byproduct called NAPQI. The researchers discovered that the amount of NAPQI produced varied throughout the day.The amount of NAPQI produced may fluctuate by as much as 50 percent, depending on the time of day the medication is given. Additionally, it was discovered that atorvastatin can result in increased toxicity at specific times of the day.
Both of these medications are partially metabolized by an enzyme known as CYP3A4, which operates on a circadian cycle. CYP3A4 plays a role in the processing of approximately half of all medications, prompting the researchers to plan more tests on these drugs using their liver models.
“For this group of medications, it would be beneficial to determine the optimal time of day for administering the drug in order to achieve maximum effectiveness while minimizing potential side effects.””Negative effects,” March says.
The researchers from MIT are currently collaborating with others to study a cancer medication that they believe may be impacted by circadian rhythms, and they hope to explore whether this could also apply to pain management drugs.
Vulnerability to infection
Many of the liver genes that exhibit circadian patterns are involved in immune responses, such as inflammation, so the researchers questioned whether this variation might affect susceptibility to infection. To address that inquiry, they exposed the modified livers to Plasmodium falciparum, a parasite that causes malaria, at different times of day.
Research has shown that the time of day when exposure occurs affects the likelihood of liver infection. This is because of the differences in the expression of interferon-stimulated genes, which play a role in suppressing infections.
Lead researcher Bhatia explains, “Inflammatory signals are stronger at certain times of day, making it easier for viruses like hepatitis or parasites like those causing malaria to take hold in the liver.”
The study suggests that the liver’s response to infection may vary throughout the circadian cycle.In response to pathogens after meals, the liver is often exposed to a large number of microorganisms that can cause inflammation, regardless of whether they are actually harmful.
Bhatia’s lab is now using these cycles to investigate infections that are typically difficult to establish in engineered livers, such as malaria infections caused by parasites other than Plasmodium falciparum.
“This is a significant development for the field, as simply setting up the system and selecting the right time of infection can increase our culture’s infection rate by 25 percent, making drug screens feasible,” said Mar.ch says the research was funded by the MIT International Science and Technology Initiatives MIT-France program, the Koch Institute Support (core) Grant from the U.S. National Cancer Institute, the National Institute of Health and Medical Research of France, and the French National Research Agency.
