Cytochrome P450 Pathway


The Cytochrome P450 Pathway, the History, and Possible Drug Interactions

Tricia Siletti

13 August 2019


Current culture health care strategy calls for a variety of pharmaceuticals and herbs that are often taken together in order to try to take care of ailments. Often, these pharmaceutical drugs and herbs may interact with each other and metabolism occurs via a group of enzymes referred to as the cytochrome P450 pathway. The cytochrome P450 pathway metabolizes drugs and herbs and may either induce or inhibit their effects. This review of current research suggests that the protein enzymes that have evolved along the P450 pathway are responsible for herbal and pharmaceutical interaction and that this interaction can be influenced by one’s genetic makeup, age, race, or environmental factors.  

 

Introduction


The cytochrome P450 pathway is impressive. It is in every living thing on earth from bacteria to mammals. Cytochrome P450 is a superfamily of proteins evolving from over many billions of years ago. Cytochrome P450 (CYP) contains heme enzymes that function as monooxygenases. Monooxygenases are enzymes that incorporate on hydroxyl group into substrates (McDonnell, 2013). These enzymes are located throughout the body and are involved in chemical activation, deactivation, and carcinogenesis. The cytochrome pathway can be inhibited or induced by drugs or herbal interactions and may be responsible for possible adverse reactions. Knowledge of the possible drug/herbal interactions along the pathway should help to minimize the chances of negative drug reactions or interactions. 


The P450 refers to the wavelength absorption of the heme enzymes at 450nm when in a reduced state and complexed with carbon monoxide.  It has been postulated that the first cytochrome P450 gene would have been prior to the existence of eukaryotes and before oxygen in the atmosphere. (Danielson, 2002) Roughly 2.8 billion years ago, ancient cytochrome P450s may have been used to support early life forms movement from sea to land. The toxic oxygen filled air would have killed these early creatures had P450 not been there to mediate oxygen levels making the toxic gas more tolerable. Mutations of the P450 gene come over the course of the next billions of years ensuring that creatures are able to metabolize energy needed for survival. One such mutation may have occurred 1.5 billion years ago creating several of the ancestral pathways such as CYP11 and CYP4. These pathways are known to be those involved in the metabolism of fatty acids, cholesterol and its derivatives. (Danielson, 2002)  Other pathways may be responsible for fundamental functioning of the organism including electrolyte balance, cell division, mating, and ligand activation. 


The first discovery of CYP was in 1954 when Klingenberg was conducting research on steroid hormone metabolism. Kliongenberg was able to extract a new protein from hepatocytes. It wasn’t until 1963 that another group of scientists, Estabrook, Cooper, and Rosenthal, described CYP as a main catalyst in drug metabolism (Lynch, 2007) . Since these initial discoveries, the importance of CYP has grown and science has had to classify similar gene sequences in order to differentiate them. Today, there have been at least 57 chromosome P450s identified. These genes are then categorized into 18 families and 43 subfamilies. Each family presents a different function but all rely on metabolism as their method. CYP 1,2, and 3 focus on drug metabolism (Danielson, 2002). 


Cytochrome P450 pathways are categorized by using similar gene sequences that are then assigned a family number and a subfamily letter. They are then differentiated by using a number for each enzyme (i.e. CYP1A1 or CYP2D6). Typically drugs that work along the same pathway have more potential for drug-drug interactions; however, not all drugs use the CYP for metabolism. 

Results


Understanding the cytochrome P450 system is essential for any person working with individuals and drugs or herbs. Drug metabolism can occur all over the body and not just in the liver. The importance of CYP is to understand how drugs with CYP activity may be categorized as either inducers or inhibitors. Drugs that inhibit a pathway may cause other drugs effects to be increased. Conversely, drugs that induce the CYP may reduce other drug effects of those metabolized along the same pathway (Mcdonnell, 2013). This is significant so as to avoid possible fatal interactions or even just interactions that may cause a drug to have lowered or nil effects. 


Cytochrome P450 have their history as far back as time. This is extremely significant as it helps us to understand that these enzymes play an important role in the functioning of life. They are not new to the animal kingdom and as such have evolved into efficient heme proteins that are able to help us maintain our overall health by mediating and metabolizing the effects of potential toxins, especially pharmaceuticals.


What is also of interest is how or why individuals process toxins differently. It seems that while each CYP has a specific function, how it functions in each individual may be affected by environmental factors such as diet, prior exposure to other drugs, tobacco consumption, and alcohol consumption (Danielson, 2002). These factors may also be compounded by one’s ethnicity or sex. One study found that one out of every 15 white or black people may have an exaggerated response to beta blockers but no response to Ultram/tramadol. This was not found to be true in other ethnicities. Drug metabolism via the cytochrome P450  pathway exhibits genetic variability and may create pseudogenes that affect the individual's response to a drug. A similar study determined that 7% of white people and 2-7% of black people are poor metabolizers of drugs dependent on CYP2D6, which metabolizes beta blockers, antidepressants, and opioids. One in five Asians are poor metabolizers of drugs dependent on CYP2C19, which helps to metabolize drugs such as dilantin, phenobarbital, and omeprazole. This variance is possible due to enzyme polymorphism or can be caused by genetic variations in other drug metabolizing enzymes, transporters, or receptors (Lynch, 2007). 


Drug interactions are common. A 2008 review reported that of the most commonly sold pharmaceuticals sold in the United States, a majority ran through the liver and of those, most involved enzymes from the first three CYP families. In fact, the most commonly used pathways for metabolism are CYP3A4/5, CYP2C9, and CYP2C19 (McDonnell, 2013). It is also important to note that drugs may still interact despite following different enzyme pathways. A 2010 observational study reported that women with breast cancer were more likely to die from the cancer if treatment was tamoxifen and the tamoxifen was tainted by ingesting the drug paroxetine. Paroxetine is a selective serotonin reuptake inhibitor (SSRI). This findings of this study support the notion that SSRIs have inhibitory activity along the CYP2D6 pathway. Similarly, grapefruit juice also inhibits CPY3A4 which will affect all those drugs interacting with CYP3A. When codeine was given to patients carrying CYP2D6 gene duplication, 50% more morphine was produced. This may have been the case when a breastfeeding mother was prescribed codeine and as a result, her baby suffered morphine toxicity and died (McDonnell, 2013 ).  Consequences of these amplified interactions may vary but if death may potentially be a result, then one cannot be too careful with ensuring that negative drug interactions are limited. 


Herbs also possess the inducing or inhibiting effect on the cytochrome P450 pathway. In a 2018 study (Dong, 2018) on the inhibitory effects of bergenin Bergenia purpurascens, an antitussive, anti inflammatory, wound healer, it was found that bergenin affects the metabolism across the CYP1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8 pathways. This study sought to understand the relationship of drugs that may be prescribed. Our culture lives in a world of multi-drug therapy, which in some cases may present advantages, and in others inhibitions. While the study admits that future research is warranted on this topic, it is clear that the pathway enzymes metabolize more than pharmaceuticals and that herbs can also affect the metabolics of several avenues, mainly the transports CYP3A4, 2E1 and 2C9 on the pathway. 


A 2008 study determined that there is a life threatening herbal interaction between warfarin and cranberry juice. The research looked at a connection between warfarin and garlic and warfarin and cranberry to test a pharmacodynamic interaction. It was found that the warfarin and cranberry juice combination showed evidence of a reduction in clotting factors. Subjects experienced symptoms of excessive bleeding in some cases. The research found that when cranberry juice concentrate was given pre-warfarin treatment, no signifcant symptoms were encountered. However, when administered concurrently with warfarin, subjects did experience symptoms of excessive bleeding. The study also determined that individuals with the VKORC1 genotype may be more likely to show symptoms. This illustrates that only certain subjects may be affected by the garlic-warfarin or the cranberry juice-warfarin interaction. These findings are significant as they show that two relatively innocuous herbal remedies has a pharmacodynamic interaction and that may potentially be fatal in certain subjects. 





Conclusion


Since its discovery in the 1950’s, it has become quite clear that there is an important need to understand the cytochrome P450 pathway. The pathway is billions of years old and can be found in all living beings. This can only explain how fundamental the heme proteins are in ensuring we can maintain life and not be fatally subjected to toxins we may encounter. Future study on possible interactions and how to avoid toxic interactions. 



References: 


Cassady, B. (2019) Spotlight on Substances: St. JOhn’s Wort. Environmental Nutrition. Retreived from http://web.b.ebscohost.com/ehost/pdfviewer/pdfviewer?vid=3&sid=c5104afe-c676-4c45-afd2-c655f9ebdbd5%40pdc-v-sessmgr06 


Cho, H., Yoon, I. (2015)Pharmacokinetic Interactions of Herbs with Cytochrome P450 and P-Glycoprotein. Evidence-Based Complementary and Alternative MedicineVolume 2015, Article ID 736431, 10 pages

http://dx.doi.org/10.1155/2015/736431


Danielson, P.B. (2002) The Cytochrome P450 Superfamily: Biochemistry,Evolution, and Drug Metabolism in Humans. Current Drug Metabolism, 2002, 3, 561-597. http://scholar.google.com/scholar_url?url=https://www.researchgate.net/profile/Phillip_Danielson/publication/11089661_The_Cytochrome_P450_Superfamily_Biochemistry_Evolution_and_Drug_Metabolism_in_Humans/links/09e415084bd9110cf1000000.pdf&hl=en&sa=X&scisig=AAGBfm2_tZRWYUAmfx79llPWYzkg9sli9w&nossl=1&oi=scholarr


de Lima Toccafondo Vieira, M., Huang, S. (2012) botanical Drug Interactions: A Scientific Perspective. Plant Med 2012: 78(13): 1400-1415. https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0032-1315145


Dong, G., Zhou, Y., & Song, X. (2018). In vitro inhibitory effects of bergenin on human liver cytochrome P450 enzymes. Pharmaceutical Biology, 56(1), 620–625. https://doi.org/10.1080/13880209.2018.1525413


Gurley, B. J., Gardner, S. F., Hubbard, M. A., Williams, D. K., Gentry, W. B., Cui, Y., & Ang, C. Y. (2005). Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John's wort, garlic oil, Panax ginseng and Ginkgo biloba. Drugs & aging, 22(6), 525–539. doi:10.2165/00002512-200522060-00006


Johansson, I., Ingelman-Sundberg, M. (2011) Genetic Polymorphism and Toxicology—With Emphasis on Cytochrome P450, Toxicological Sciences, Volume 120, Issue 1, March 2011, Pages 1–13, https://doi.org/10.1093/toxsci/kfq374


Lynch, T., Price, A. (2007) The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects. Virginia Am Fam Physician. 2007 Aug 1;76(3):391-396.  https://www.aafp.org/afp/2007/0801/p391.html 


McDonnell, A. M., & Dang, C. H. (2013). Basic review of the cytochrome p450 system. Journal of the advanced practitioner in oncology, 4(4), 263–268.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4093435/


Mohammed Abdul, M.I., Jiang, X., Williams, K.M., Day, R.O., Roufogalis, B.D., Liauw, W.S., et al. (2008) Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects.  Br J Pharmacol. 2008;154:1691–1700.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518459/?report=reader  


Wanwimolruk, S., & Prachayasittikul, V. (2014). Cytochrome P450 enzyme mediated herbal drug interactions (Part 1). EXCLI journal, 13, 347–391.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463967/


Zhou, S. Gao, Y., Jiang W., Huang M., Xu, A., Paxton, J. (2003) Interactions of Herbs with Cytochrome P450 Drug Metab Rev. 2003 Feb;35(1):35-98 https://www.ncbi.nlm.nih.gov/pubmed/12635815