A new study conducted by researchers from the Massachusetts Institute of Technology (MIT) has revealed that circadian variations in liver function play an important role in influencing drugs’ effectiveness.
Published in Sciences Advances, researchers found that many genes involved in drug metabolism are under circadian control, affecting drug efficacy in the body.
Circadian variations are the natural cycle of physical, mental and behavioural changes that the body experiences in a 24-hour cycle and can affect how effectively the body can break down a drug.
An estimated 50% of human genes follow a circadian cycle, many of which are active in the liver.
Researchers from MIT and Rockefeller University identified culture conditions that supported the circadian expression of a clock gene known as Bmal1, which regulates the cyclic expression of a variety of genes.
Using tiny, engineered livers derived from cells from human donors, the researchers found that the Bmal1 gene allowed the liver cells to develop synchronised circadian oscillations.
After measuring the gene expression of these cells, researchers were able to identify more than 300 liver genes that follow a circadian clock, 70% of which peaked together and included genes involved in drug metabolism, glucose and lipid metabolism and several immune processes.
Researchers then used these circadian cycles to explore how they affected liver function using two different drugs: acetaminophen (Tylenol) and atorvastatin, a drug used to treat high cholesterol, which are both metabolised in part by an enzyme called CYP3A4, a circadian cycle.
They discovered that the amount of a toxic by-product known as NAPQI, which occurs when Tylenol is broken down in the liver, could vary by up to 50% depending on the time of day the drug is administered. In addition, atorvastatin was found to generate higher toxicity at certain times of day.
Researchers now plan to test more drugs using liver models to understand their circadian cycles, including a cancer drug that is suspected to be affected by circadian cycles.
