Long Covid Part 11 The Genetic Basis to Improving Toxin Detoxification
Your genetics determine if the body can clear toxins efficiently.
Dr Valerio Vittone (PH.D) January 2023
Clearance of toxic compounds also impacts your brain and mental health and helps to fight inflammation, including allergies & immune dysfunctions, ageing, cancer, and many other conditions.(1),(3) Our body has several “lines of defence” to eliminate potentially toxic molecules. These toxins fall broadly into two categories(1),(2)
1. Endotoxins: These are “internal” by-products of our metabolism. These also include endogenous compounds produced by bacteria living in our gut, mouth and other tissues (i.e. bacterial endotoxins).
2. Exotoxins: These are all the “external” toxic compounds that we are exposed every day in our lives. The most significant include(2),(3)
Over The Counter (OTC) medications
recreational substances (e.g. MDMA, Cocaine
agricultural compounds including pesticides and insecticides
polycyclic aromatic amines (PAA) ( e.g. brown layer on Charred meat, car exhaust fumes and cigarette smoke)
polycyclic aromatic hydrocarbons (PAH) (e.g. present on Charred beef cooked on the barbeque, vehicles exhaust fumes and cigarette smoke)
aluminium (homeware & deodorant)
Bisphenol-A (BPA) Plastic not certified “BPA free”, lining inside food cans
Micro-organisms (e.g. bacteria, fungi, Viruses)
What happens during detoxification
The first line of defence is in the liver (but also present in the mucosal surface of the intestinal tract), and it is a collection of enzymes belonging to the cytochrome P450 family.
These enzymes, are involved in a process called PHASE I detoxification . PHASE I enzymes “transforms” compounds like xenobiotics, pharmaceutical and steroid hormones such as Oestrogen in new molecules.(4)
These new molecules also called “intermediates” are more water-soluble, and the body can more efficiently process them in a second stage called PHASE II.
During PHASE II, additional enzymes “attach specific molecular tails” to these intermediate break down products in a process called “conjugation”. This transformation makes these molecules, even more, water-soluble (List of critical enzymes involved in conjugation below).
At this stage, modified metabolites are ready for disposal via the bile and kidneys. Elimination finally occurs through Faeces/stools and urine.(2)
Recent studies have shown that several genetic factors (SNP) determine if you are “fast” or “slow” to break down toxins.
Antidepressant, beta-blockers, opioid, Non-Steroidal Anti-inflammatory Drugs (NSAID) (e.g. Aspirin) are some of the drugs that can cause problems.(2),(6)
Researchers have also found that only a few enzymes belonging to the P450 family break down approximately 70% of all medications that affect the mind.(6)
Scientists discovered that 70% of the population has at least one of these genetic variants (SNPs).(6),(7)
Also, up to 40-60% of individuals have adverse drug reactions.(2),(6)
Remember that you inherit these SNPs from your Maternal and Paternal DNA.
A comprehensive gene testing system can help you to determine potential adverse drug and other toxins side effects caused by your genetic variation. In science, we call the relationship between genetic factors and drug response Pharmacogenetics.
These are few of the most critical SNPs identified by current research and pharmacogenetic studies that effects PHASE I and PHASE II detoxification:
PHASE I DETOXIFICATION
Four STAGE I CYPs metabolise almost all hepatic drugs.
They are CYP2D6, CYP2C9, CYP2C19, and CYP3A4 6.
CYP2D6, CYP2C9, and CYP2C19—metabolise approximately 70 % of all psychotropic drugs
CYP2D6 involved in breaking down 25% of all clinically used medicines like opioids, beta-blockers, antidepressants, anti-psychotics and tamoxifen (i.e. Breast Cancer medication). It is also involved in the synthesis of the “Reward & Pleasure and feels good” hormones dopamine and serotonin.(3),(8)
CYP2C9 important during the metabolism for Warfarin, Crestor (statin medication), NSAIDs and clearance of THC, the psychoactive compound in cannabis.(11),(12)
CYP2C19 is responsible for the breakdown of several popular acid reflux drugs like Nexium. Also, CYP2C19 both activates and breaks down the female hormone progesterone. Popular antidepressants, Zoloft and Lexapro, are also broken down mainly through CYP2C.(19),(13)
CYP1A2 involved in breaking down caffeine amongst other drugs.(10)
CYP3A4 involved in breaking down a large number of prescription drugs, including erectile dysfunction meds Viagra and Cialis and anxiety medication Xanax.(9)
PHASE II GLUTATHIONE CONJUGATION & ACETYLATION KEY GENE VARIANTS (SNPs).
GSTP1 removes the toxic compounds from mucosal membranes (breast, bowel, lungs, bladder, sinuses) and skin fighting inflammation, decreasing the risk of eczema, asthma, IBS, cystitis, lung heath.(3),(14)
GSTM1 removes the toxic and carcinogenic compounds from inside the cells. It is associated with joint diseases like rheumatoid arthritis and several cancers.(15)
GSTM3 removes cytotoxic and carcinogen agents from the brain, and it is associated with dementia.(16)
NAT2 is involved in adding a “molecular tail” in a process called “acetylation” engaged in breaking down various harmful chemicals present in the diet and industrial carcinogens (e.g. PAAs and PCBs).(3)
KEY (SNPs) AGAINST OXIDATIVE STRESS INVOLVED IN DETOXIFICATION.
SODs (step1), CATs (step 2) and GPXs (step 3) sequentially are the main line of defence to convert harmful Reactive Oxygen Species (ROS) also known as free radicals to less toxic chemicals such as hydrogen peroxide (H2O2) and harmless water (H20).(17)
It is important to note that GPX enzymes work in combination with Glutathione “The Master Antioxidant”. This fantastic “free radical scavenger” is also used by GSTPs enzymes during conjugation (described in PHASE II above)(3),(14),(15),(16)
SOD1 is an “antioxidant” that our body uses to convert “superoxides” (a very reactive species) into hydrogen peroxide (H2O2) broadly inside our cells. SOD1 protects against conditions such as diabetes, kidney disease, and hearing damage.(18),(19)
SOD2 is the manganese dependent “defender” protecting against “superoxides” (a very reactive species) inside the mitochondria of cells. It is crucial for heart & bone health, stable blood sugars, male fertility and clearing of cancer cells.(18)
SOD3 is zinc/copper-dependent enzyme and protects against “superoxides” outside of cell membranes and connective tissues protecting the brain, lungs.(20),(21)
CAT transforms reactive hydrogen peroxide into harmless water. It prevents DNA damage caused by free radicals.(22)
GPX1 is dependent on selenium that transforms reactive hydrogen peroxide into harmless water. It is involved in protecting from osteoarthritis and cancer to many other diseases.(23),(24)
GPX3 is dependent on selenium and transforms reactive hydrogen peroxide into harmless water. It is involved in metabolic syndrome (e.g. obesity, insulin resistance).(25)
How poor lifestyle habits and by-products of PHASE I detoxification can increase the number of free radicals.
Our bodies produce free radicals when we are stressed (mentally and physically) and with a poor diet and alcohol consumption.
Also, during PHASE I processes, we produce reactive oxygen species as “by-products.”
This situation deteriorates further when gene variants (SNPs) of Phase I are not functioning correctly and toxins start to “built-up”.(3)
These un–metabolised toxins can slow down or/and compromise further transformation of these molecules by Phase II enzymes.
This “imbalance” is called “uncoupling”.
Accumulation of reactive toxins (e.g. Reactive Oxygen Intermediates), caused by uncoupling, has detrimental effects on your health.(2),(3)
ANTIOXIDANT/PROTECTIVE NUTRITIENTS/ PLANT DERIVATIVES (TO FIGHT REACTIVE OXYGEN INTERMEDIATES).(2)
Carotenes (Vit A)
Ascorbic acid (Vit C)
Tocopherols (Vit E)
Thiols (found in garlic, onions & Cruciferous vegetables)
1. “Detoxification” Luke Fortney MD, FAAFP, Rian Podein MD, Michael Hernke PhD, in Integrative Medicine (Fourth Edition), 2018, https://www.sciencedirect.com/topics/medicine-and-dentistry/detoxication
2. Liska DJ. The detoxification enzyme systems. Alt Med Rev 1998;3(3):187-198, http://www.altmedrev.com/archive/publications/3/3/187.pdf
3. “What can genes tell us about children’s toxicity risk?” Belinda Reynolds Fx-Medicine February 8, 2018, https://www.fxmedicine.com.au/blog-post/what-can-genes-tell-us-about-childrens-toxicity-risk
4. Hodges RE, Minich DM. Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application. J NutrMetab. 2015;2015:760689. doi:10.1155/2015/760689
5. William E. Evans, Pharm.D., and Howard L. McLeod, Pharm.D. Pharmacogenomics — Drug Disposition, Drug Targets, and Side Effects. N Engl J Med 2003; 348:538-549 DOI: 10.1056/NEJMra020526, https://www.nejm.org/doi/10.1056/NEJMra020526
6. David Durham, Utilizing Pharmacogenetics in Psychiatry: the Time Has Come. Mol Diagn Ther, 2013 18:117, https://link.springer.com/article/10.1007%2Fs40291-014-0085-4
7. Relling MV, Klein TE. CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. ClinPharmacol Ther. 2011;89(3):464–7.
8. Hiroi, Toyoko & Imaoka, Susumu & Funae, Yoshihiko. (1998). Dopamine Formation from Tyramine by CYP2D6. Biochemical and biophysical research communications. 249. 838-43. 10.1006/bbrc.1998.9232.
9. John R. Horn, PharmD, FCCP, and Philip D. Hansten. Get to Know an Enzyme: CYP3A4. PharmD, January 9 2018, https://www.pharmacytimes.com/publications/issue/2008/2008-09/2008-09-8687
10. Flockhart DA (2007). “Drug Interactions: Cytochrome P450 Drug Interaction Table”. Indiana University School of Medicine. https://druginteractions.medicine.iu.edu/Home.aspx
11. Watanabe K1, Yamaori S, Funahashi T, Kimura T, Yamamoto I. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007 Mar 20;80(15):1415-9.https://www.ncbi.nlm.nih.gov/pubmed/17303175
12. Lin J, Zhang Y, Zhou H, Wang X, Wang W. CYP2C9 Genetic Polymorphism is a Potential Predictive Marker for the Efficacy of Rosuvastatin Therapy. ClinLab. 2015;61(9):1317-24. https://www.ncbi.nlm.nih.gov/pubmed/26554252
13. Hicks JK et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. ClinPharmacol Ther. 2015 Aug;98(2):127-34.https://www.ncbi.nlm.nih.gov/pubmed/25974703
14. MacIntyre EA, Brauer M, Melén E, et al. GSTP1 and TNF Gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) study. Environ Health Perspect 2014;122(4): 418-424.https://www.ncbi.nlm.nih.gov/pubmed/24465030
15. Emeli Lundström et al. Effects of GSTM1 in Rheumatoid Arthritis; Results from the Swedish EIRA study. PLOS ONE, March 22 2011. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017880
16. Peter Ponomarenko1et al. Candidate SNP Markers of Familial and Sporadic Alzheimer’s Diseases Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters. Front. Aging Neurosci., 20 July 2017. https://www.frontiersin.org/articles/10.3389/fnagi.2017.00231/full#h1
17. Peng, Cheng & Wang, Xiao Bo & Chen, Jingnan & Jiao, Rui & Wang, Lijun & Li, Charis & Zuo, Yuanyuan & Liu, Yuwei & Lei, Lin & Ma, Ka & Huang, Yu & Chen, Zhen-YU. (2014). Biology of Ageing and Role of Dietary Antioxidants. BioMedresearch international. 2014. 831841. 10.1155/2014/831841.https://www.ncbi.nlm.nih.gov/pubmed/24804252
18. Neves AL, Mohammedi K, Emery N, Roussel R, Fumeron F, Marre M, Velho G. Allelic variations in superoxide dismutase-1 (SOD1) gene and renal and cardiovascular morbidity and mortality in type 2 diabetic subjects. Mol Genet Metab. 2012 Jul;106(3):359-6https://www.ncbi.nlm.nih.gov/pubmed/22608880
19. Hadjadj S, Marre M, Velho G. Allelic variations in superoxide dismutase-1 (SOD1) gene are associated with increased risk of diabetic nephropathy in type 1 diabetic subjects. Mol Genet Metab. 2011 Dec;104(4):65460.https://www.ncbi.nlm.nih.gov/pubmed/21963083?dopt=Abstract
20. Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression.Free Radic Biol Med. 2002 Aug 1;33(3):337-49.https://www.ncbi.nlm.nih.gov/pubmed/12126755
21. Marklund SL. Extracellular superoxide dismutase in human tissues and human cell lines. J Clin Invest. 1984 Oct;74(4):1398-403.https://www.ncbi.nlm.nih.gov/pubmed/6541229
22. 27] Selvaratnam J, Robaire B (November 2016). “Overexpression of catalase in mice reduces age-related oxidative stress and maintains sperm production”. Exp. Gerontol. 84: 12–20. doi:10.1016/j.exger.2016.08.012. PMID 27575890.
23. Huang L1, Shi Y, Lu F, Zheng H, Liu X, Gong B, Yang J, Lin Y, Cheng J, Ma S, Lin H, Yang Z.Association study of polymorphisms in selenoproteingenes and Kashin-Beck disease and serum selenium/iodine concentration in a Tibetan population.PLoS One. 2013 Aug 23;8(8):e71411.https://www.ncbi.nlm.nih.gov/pubmed/24058403?dopt=Abstract
24. Cheng TY, Barnett MJ, Kristal AR, Ambrosone CB, King IB, Thornquist MD, Goodman GE, NeuhouserML. Genetic variation in myeloperoxidase modifies the association of serum α-tocopherol with aggressive prostate cancer among current smokers. J Nutr. 2011 Sep;141(9):1731-7.https://www.ncbi.nlm.nih.gov/pubmed/21795425?dopt=Abstract
25. Baez-Duarte BG et al. Glutathione peroxidase 3 serum levels and GPX3 gene polymorphisms in subjects with metabolic syndrome. Arch Med Res. 2014 Jul;45(5):375-82.https://www.ncbi.nlm.nih.gov/pubmed/24819036?dopt=Abstract