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Liver, Metabolism, Detox Capabilities, and Diurnal Oscillation
Like many biological processes in the body, liver functions are influenced by circadian rhythms. These rhythms regulate lipid, bile, cholesterol, alcohol, and drug metabolism. Hepatic clock gene expression is influenced by both internal and external cues that help regulate liver function. However, rhythm dysfunction can disrupt xenobiotic detoxification and may contribute to metabolic diseases and certain cancers. Because liver function is critical for lipid homeostasis and proper detoxification, optimal and balanced circadian rhythms are important to maintain.
PARbZip proteins are important circadian transcription factors with roles in metabolism and hepatic detoxification. In particular, there are three PARbZip transcription factors controlled by CLOCK and BMAL1 in the liver that regulate detoxification: D-site binding protein, thyrotrophic embryonic factor, and hepatic leukemia factor. Studies have found that knockout mice without these genes cannot metabolize xenobiotics due to a dysregulation of the enzymes and regulators involved in phase I and II detoxification. These genes activate cytochrome P450 oxidoreductase. They also power the daily oscillations of these pathways, especially those controlled by the CYP systems.
Enzymes affected in the liver by the circadian master control include:
– Metabolism of carbohydrates: PEPCK, PKLR, KLF10
– Metabolism of lipids: PPAR, PGC1, LXR
– Metabolism of amino acids: KLF15, OCD
– Detoxification: TEF, HLF, DBP
– Plasma protein synthesis: TFPI
– Metabolism of bile acids: SREBP, INSIG
In addition to liver enzymes, bile acids follow a circadian rhythm controlled by the central clock. They play an important role in the digestion and absorption of dietary fat, fat-soluble vitamins, steroids, and certain drugs. They also act as signaling molecules for metabolism and immune modulation. CYP7A1, the gene that regulates the synthesis of bile acids, peaks in the middle of the active period and reaches its minimum in the middle of the rest period. In humans, there are two peaks: 1:00 p.m. and 9:00 p.m. Most bile acid synthesis occurs right after eating.
There are three detoxification phases, each with its own regular schedule. Phase I requires the CYP genes, which have 18 different families. Humans have 57 CYP genes, with various families responsible for the metabolism of different molecules. For example, CYP1 genes are largely responsible for metabolizing xenobiotics and drugs. CYP enzymes increase their activity during the active phase. Conversely, phase II and III enzymes peak during the rest phase. This impacts the ability to metabolize drugs and might impact the body’s ability to detoxify other xenobiotics. For many drugs, morning intake makes it easier to absorb the drug, since it is the time at which bile acid synthesis hits a peak, helping to facilitate the absorption and transportation of the drug.
Maximizing Medications and Supplement Use Through Circadian Rhythms
Certain medications are more effective and less toxic when given at different times of the day, such as immunomodulators, glucocorticoid steroids, insulin for type-1 diabetics, cancer drugs, and more. For example, P-glycoprotein or P-gp mRNA expression in the liver and intestines, which plays a role in the detoxification of a certain cancer medication known as irinotecan, was found to have changes dependent upon time of day. The efficacy and tolerance of the drug related to the diurnal changes, with the timing of the highest expression of the mRNA corresponding to the best tolerability and effectiveness of the drug. This finding has led to the development of chronopharmacology, or taking medication at appropriate times in the circadian rhythm. Chronopharmacology takes into account the daily timing of essential components of drug metabolism:
- Absorption: timing of blood flow, gut motility, emptying of the gut, transporters of the medication, and pH
- Metabolism: cytochrome P450 enzyme activity, conjugating enzyme activity, ATP-binding cassette transporters
- Genes targeted by drugs: neural receptors, HMG-CoA reductase
- Distribution: lipophilicity, affinity for binding with albumin, concentration
- Excretion: glomerular filtration rate, renal blood flow, function of the kidneys
Matching medication usage with the natural circadian rhythms has a major impact on its efficacy and safety. In an older meta-analysis, taking medications on a schedule that matches circadian cycles led to a 5-fold enhanced tolerance of the drug and twice the efficacy of the drug compared to the same treatment not on a schedule. Similar instances occur with metabolism and the detoxification of other xenobiotics. Newer research is exposing the effects of drugs and the diurnal oscillations of the blood-brain barrier, creating innovative discussions surrounding chronotherapeutics. Like chronopharmacology, chronotherapy (i.e., synchronizing medications, light exposure, lifestyle, and food with circadian rhythms) is a growing field with numerous applications yet to be discovered for human health.
Circadian rhythms may also dictate what times certain nutritional supplements should be taken. For example, the timing of a calcium supplement might impact its effect on bone resorption. In one study on 18 premenopausal women, the patients took calcium supplements at either 8:00 a.m. or 11:00 p.m. After 14 days, urine collections were studied to review markers of bone resorption. They found that the time of day had a significant effect, with evening calcium intake suppressing the usual nightly increase in parathyroid hormone and markers of bone resorption. Morning supplementation had no impact. Therefore, taking calcium in the evening could suppress bone resorption.
Although research into the timing of supplement dosage is not as robust as that reviewing the impact on medication, the diurnal rhythms of digestion, metabolism, and detoxification systems will impact the efficacy of any substances, including nutritional supplements. As such, it is beneficial to bear this in mind and ensure a balanced and functional circadian rhythm.
Before making any changes in the diet, supplementation, and lifestyle, talk to a doctor, nutritionist, dietitian, or healthcare team member. Personal options should be based on individual circumstances, conditions, medications, and health needs.
