Circadian rhythms and drug metabolism

Thought we’d revisit a cool paper from This Week in Science. The idea that when in the day we take different drugs makes a difference in their effectiveness deserved a deeper look (aka this is a good way to make myself read the paper).

The Problem

We operate on 24 hour cycles, not just in our daily lives, but at the cellular level. Our cells and organs act and function differently based on what time it is. We feel this through things like sleepiness, but what about the things we don’t feel?

What cyclic circadian differences effect things like drug metabolism?

This week’s paper is a small but significant step towards answering that question. The authors set up a cell culture system to study human liver cells (called hepatocytes), explore how they change in 24 hour cycles, and see how these changes influence their response to drugs and stimuli.

The Paper

The liver plays an important role in the body, helping with metabolism, digestion, and immune responses. And more importantly for today, it’s heavily influenced by our circadian rhythms. Roughly 50% of human genes change their expression in a 24-hour cycle. They’re controlled in large part by “core clock genes” such as Bmal1 and the aptly named… Clock gene. They forced the Clock acronym a little bit, but we’ll forgive them.

In their liver hepatocyte model, the authors were able to get the cells to exhibit a 24-hour circadian-like cycle of Bmal1 expression for at least 10 weeks. They could even precisely control the timing of these rhythms based on when and what they fed the cells, resulting in different cultures being in different phases of the cycles (shown above).

Disrupting the cells circadian cycle by silencing the Bmal1 master gene effected gene expression related to drug metabolism and inflammatory signaling. It’s hard to say what the physical meaning behind these changes are, but it’s important to note the change. The obvious, and debatably too far, extrapolation is that disrupted sleep cycles can effect our bodies too.

In their culture system, the researchers found that roughly 25% of the genes most heavily involved in drug absorption, distribution, metabolism, and excretion (the ADME genes) “oscillate in circadian patterns”.

You can see this quite clearly in the example below. The CYP3A4 gene is clinically relevant for its role involved in drug metabolism. It’s responsible for the elimination of many drugs from the body. As you can see, its activity closely follows a ~24 hour cycle, peaking in 12 hour increments.

In the final experiment I want to mention today, the authors looked at how the circadian cycle effects our susceptibility to infections. To do this, they infected their cultures with malaria causing parasites at different points during their circadian cycle.

You might not be surprised, but they did indeed find a difference. Cells exposed to the parasite at “circadian time 24 hours” were roughly twice as likely to get infected as those exposed at 36 hours. The researchers hypothesized that this was due to the larger presence of inflammatory markers at 36 hours compared to 24 hours, indicating a better immune response to the infection.

While they don’t provide us with practical insights yet, studies like this one are establishing that timing can be critical for drug performance. I bet it wont be long before clinical trials start testing time of day in their studies and we get some answers.

Until then, here’s an interesting piece I found about taking timing into account in medicine.

See you next week for more science,

Neil