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Cytochrome P450 enzymes in drug metabolism
Drug metabolism is a complex biological process involving an extensive network of enzymes, conjugates, and elaborate biochemical pathways. Cytochrome P450 enzymes are membrane-bound (cyto) enzymes containing a heme pigment (chrome and P) absorbing light at a wavelength of 450 nanometers when exposed to carbon monoxide. Predominantly expressed in the liver, these enzymes are produced by the cytochrome P450 genes and primarily responsible for the intracellular synthesis of steroids, cholesterol, prostacyclin, and thromboxane A2. In modern medicine, cytochrome P450 enzymes are characterized and studied with respect to their function in the metabolism of natural products, pharmaceuticals, carcinogens, and chemicals ingested into the body.
Early research studies suggest that cytochrome P450 enzymes are responsible for the metabolism of about 90% of the total drugs currently in use. Logically judging from this submission, scientists expect a reservoir of functional cytochrome enzymes inhibiting the metabolism sites of the body. Data from the human genome sequence project confirmed the existence of about 57 distinct P450 genes, including 13 orphan genes with no clear metabolic function. In some studies, these enzymes are identified and classified based on their respective substrates.
The alternative therapy approach in modern medicine has long been based on natural products derived from plant or animal origin. The proliferation of these compounds increases interests in the relationship between cytochrome P450 enzymes and the metabolic pathway of these products. For instance, the U.S. Food and Drug Administration provisions in drug testing and registration mandates a manufacturer to submit official documents detailing the specific cytochrome P450 enzymes involved in the metabolism of the drug. This information is necessary to characterize the new drug and determine potential drug-drug on drug-cytochrome P50 enzyme interactions.
Over the decades, the regulations restricting and prohibiting the use of cannabis and cannabis-derived products have been changing. In the U.S., licensed farmers are legally allowed to cultivate and market cannabis products under state-controlled programs. In sports, the World Anti-Doping Agency has removed cannabidiol from the list of prohibited substances. In the medical community, CBD is now prescribed under regulated guidelines for the management of rare and chronic diseases, including Dravet syndrome, multiple sclerosis, Parkinson’s disease, substance abuse, and Alzheimer’s disease. Recently, different research reports investigating the relationship between cannabidiol and cytochrome P450 enzymes have been published.
Interaction between cannabidiol and P450 enzymes
- Cannabinoids are extensively metabolized by cytochrome P450 enzymes
By relaxing the ban on the use of cannabis and cannabis-derived products, regulatory bodies have indirectly encouraged scientific inquiries into cannabis science. As with other natural products, phytocannabinoids have long been suggested to be metabolized by cytochrome P450 enzymes. This theory was first investigated in animal models for safety reasons. The Biological and Pharmaceutical Bulletin published the results of one of the early research studies investigating the hepatic microsomal oxidation metabolism of cannabidiol in mice. By incubating CBD with hepatic microsomes of mice in the presence of NADPH-generating systems and oxygen, researchers observed that cannabidiol is metabolized in microsomal oxidative pathways that lead to the formation of carbon monoxide.
In 2011, the result of more detailed research conducted to identify, and the specific cytochrome P450 enzymes responsible for the metabolism of cannabidiol by liver microsomes was published by the American Journal of Life Sciences. The research objectives focused on examining the in vitro metabolism of CBD with human liver microsomes. The oxidative products were analyzed and determined to consist of eight different monohydroxylated metabolites. Also, seven different cytochrome P450 enzymes (CYPs 1A1, 1A2, 2C9, 2C19, 2D6, 3A4, and 3A4) were confirmed to be responsible for CBD metabolism in the human liver (Rongrong Jigang et al., 2011).
- Cannabidiol mediates inactivation of cytochrome P450 enzymes
The interaction between the liver microsomes and CBD, in large part, is dose-dependent. As such, at varying concentrations, CBD is expected to exhibit different actions in the metabolism cycle. Preclinical observations in human subjects suggest that CBD is capable of inactivating a set of cytochrome P450 enzymes responsible for the metabolism of drugs co-administered with CBD. Studies suggest that CBD functions as a competitive inhibitor of the liver enzymes and significantly reduces the rate at which these enzymes contribute to drug metabolism. Until recently, the mechanism by which CBD exerts this inhibitory effect was unknown.
The research currently referenced in explaining this inactivation was published in 2012 in the journal Drug Metabolism and Pharmacokinetics. This research was focused on examining the effects of CBD-related compounds on cytochrome P450 enzymes. The complex research methodology indicated that CBD inhibits the hydroxylase and activities of live human microsomes and recombinant CYP2C19 (Rongrong Jigang et al., 2013).
- CBD affects the bioavailability of drugs metabolized by cytochrome P450
Drug-drug interactions are particularly important in aged patients placed on conventional drugs and on natural products as adjunctive therapy. Depending on the chemistry and metabolism pathway of the drugs, one or each of the drugs can significantly reduce the amount of the other drug, which eventually reaches the systemic circulation. By inactivating cytochrome P450 enzymes directly involved in the metabolism of drugs, CBD may reduce the bioavailability of a co-administered drug. The number of drugs affected in this relationship is still largely unknown as the science investigating the relationship between CBD and these enzymes is at its infancy. Different studies have, however, been published to explain this interaction and its effects on patients.
In 2019, the FDA received an application for a clinical trial sponsored by Johns Hopkins University. This trial is focused on investigating the interaction between cannabinoid extracts containing tetrahydrocannabinol (THC) and cannabidiol and probe drugs to select CYP450 pathways. Designed as a double-blind, randomized crossover study, this trial will investigate the extent to which high doses of CBD and THC alters the pharmacokinetics of five cytochrome P450-metabolized drugs: caffeine, losartan, midazolam, dextromethorphan, and omeprazole. With an estimated primary completion date of February 2021, this study will open up confirmed data about the effects of cannabinoid-induced CYP enzyme inhibition on drug metabolism.