EC Nutrition

One of the main interest in reviewing the detoxification processes and ability of human body to do so, is that in not being aware how to do the detoxifying process correctly, one could be faced with all sort of metabolic diseases in the course of his/her life. More and more researchers are dedicating their lives in studying these ramping diseases as each day more xenobiotics are being developed and dumped in the planet. Many protocols can be found in many different sources of information, but the foundations behind the human detox biochemistry are not so widely broadcasted. Here are presented the details.

As our external as well as our internal environment can be polluted as it gets, revisiting the mechanisms and pathways as well as the natural ways to detoxifying can be put to our service at the right time to cope with the myriads of toxic compounds we are daily exposed to. Many natural substances that provide, enhance or help the detoxification process are addressed, as well as its main biochemical pathways. The knowledge of food and soil composition and quality are forever intertwined and it is also highlighted in this work.

The 3 detox phases are explained and the scientific review on this subject presented. The influence of life style in the gene expression for the health of the emunctories are in a simple way addressed, also how diet influences them are described.

The toxins can be accumulated all over the cells in the body, but they tend to concentrate in lipophilic tissues like the brain, fat, lymphatic system, extracellular matrix and in the endocrine receptors.

 Keywords: Detox; Biotransformation; Conjugation; Elimination; Mitochondria; Leaky Gut; Mold; Parasites Cytochrome P450; Medicinal Plants

1. Mercé ALR. “Contaminated Waters and Depleted Soils: Impact in Nutrition I A review”. Advances in Complementary and Alternative Medicine (2024).
2. Tenório T and Mercé ALR. “Xenobiotics in the environment, chapter VIII”. In: Molecular and Supramolecular Bioinorganic Chemistry. Mercé, ALR & Recio, MAL Eds, Nova Publishers, USA, Volume 4 (2014): 311-339.
3. Oliveira M., et al. “Pharmaceuticals residues and xenobiotics contaminants: Occurrence, analytical techniques and sustainable alternatives for wastewater treatment”. Science of the Total Environment 705 (2020): 135568.
4. Fisher MB., et al. “The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism”. Drug Metabolism Reviews3-4 (2001): 273-297.
5. Stavropoulou E., et al. “The role of cytochromes P450 in infection”. Frontiers in Immunology 9 (2018): 00089.
6. Grant DM. “Detoxification pathways in the liver”. Journal of Inherited Metabolic Disease 4 (1991): 421-430.
7. Sasaki T., et al. “Effect of health foods on cytochrome P450-mediated drug metabolism”. Journal of Pharmaceutical Health Care and Sciences 3 (2017): 14.
8. Cytochrome P450. In: Schwab, M. (eds) Encyclopedia of Cancer. Springer, Berlin, Heidelberg (2011): 1043-1050.
9. Bibi Z. “Role of cytochrome P450 in drug interactions”. Nutrition and Metabolism (London) 5 (2008): 27.
10. Zhou Z., et al. “Hepatocytes: a key cell type for innate immunity”. Cellular and Molecular Immunology 13 (2016): 301-315.
11. Dinkova-Kostova AT and Talalay P. “Relation of structure of curcumin analogs to their potencies as inducers of Phase 2 detoxification enzymes”. Carcinogenesis5 (1999): 911-914.
12. Liang ST., et al. “Michael acceptor molecules in natural products and their mechanism of action”. Frontiers in Pharmacology 13 (2022): 1033003.
13. https://www.organic-chemistry.org/namedreactions/michael-addition.shtm
14. Mackenzie PI., et al. “UDP-Glucuronosyltransferases chapter 4.20”. In: Comprehensive Toxicology (Second Edition) Volume 4, Charlene A. McQueen ed (2010): 413-434.
15. Sakurai H and Nigam SK. “Molecular and cellular mechanisms of kidney development, Chapter 24”. In: Seldin and Giebisch's The Kidney (Fourth Edition), Academic Press, Robert J. Alpern, Steven C. Hebert eds (2008): 671-689.
16. Walesky C and Apte U. “Role of hepatocyte nuclear factor 4α (HNF4α) in cell proliferation and cancer”. Gene Expression 3 (2015): 101-108.
17. Petr P. “Pregnane X receptor (PXR)-mediated gene repression and cross-talk of PXR with other nuclear receptors via coactivator interactions”. Frontiers in Pharmacology 7 (2016): 00456.
18. Istrate MA., et al. “Regulation of CYP3A4 by pregnane X receptor: The role of nuclear receptors competing for response element binding”. Biochemical and Biophysical Research Communications 4 (2010): 688-693.
19. Laudet V and Gronemeyer H. “PXR”. Eds. Vincent Laudet, Hinrich Gronemeyer. In Factsbook, The Nuclear Receptor FactsBook, Academic Press (2002): 220-226.
20. DeKeyser JG and Omiecinski CJ. “Constitutive androstane receptor, chapter 2.10”. Ed: Charlene A. McQueen, Comprehensive Toxicology (2^nd Edition), Elsevier (2010): 169-181.
21. Mejdrová I., et al. “Discovery of novel human constitutive androstane receptor agonists with the Imidazo[1,2-a]pyridine structure”. Journal of Medicinal Chemistry 4 (2023): 2422-2456.
22. Kersten S. “Mechanisms of nutritional and hormonal regulation of lipogenesis”. EMBO Reports4 (2001): 282-286.
23. Roman-Rodriguez J., et al. “Peroxisome proliferator-activated receptors”. Eds.: Laurent GJ, Shapiro SD. Encyclopedia of Respiratory Medicine, Academic Press (2006): 327-332.
24. Laudet V and Gronemeyer H. “FXR”. Eds: Laudet V, Gronemeyer H. In: Factsbook, The Nuclear Receptor FactsBook, Academic Press (2002): 199-203.
25. Karlic H and Varga F. “Mevalonate Pathway”. Eds.: Boffetta P, Hainaut P. Encyclopedia of Cancer (Third Edition), Academic Press (2019): 445-457.
26. Jones PM and George AM. “The ABC transporter structure and mechanism: perspectives on recent research”. Cellular and Molecular Life Sciences 61 (2004): 682-699.
27. Wilkens S. “Structure and mechanism of ABC transporters”. F1000Prime Reports 7 (2015): 14.
28. Josyter Beek AG and Slotboom DJ. “Structural diversity of ABC transporters”. Journal of General Physiology 4 (2014): 419-435.
29. Beis K. “Structural basis for the mechanism of ABC transporters”. Biochemical Society Transactions 5 (2015): 889-893.
30. Duchen MR. “Mitochondria in health and disease: perspectives on a new mitochondrial biology”. Molecular Aspects of Medicine 4 (2004): 365-451.
31. Liu Y., et al. “An overview: The diversified role of mitochondria in cancer metabolism”. International Journal of Biological Sciences 3 (2023): 897-915.
32. Wang X., et al. “Mitochondrial metal ion transport in cell metabolism and disease”. International Journal of Molecular Sciences 14 (2021): 7525.
33. Tenório T and Mercé ALR. “Chapter 6. Aluminium, adenosine-5′-triphosphate, phosphocreatine and amino acids: how they can be related to some neurodegenerative diseases”. In: Molecular and Supramolecular Bioinorganic Chemistry. Applications in Medical and Environmental Sciences. Volume 4, Mercé ALR, Recio MAL Eds., Nova Science Publishers, New York (2014): 205-285.
34. Szyfman NW., et al. “Chapter 7. Polyamines, metal ions and neurodegenerative diseases: some chemical and biological aspects”. In: Molecular and Supramolecular Bioinorganic Chemistry. Applications in Medical and Environmental Sciences Volume 4, Mercé ALR, Recio MAL Eds., Nova Science Publishers, New York (2014): 287-309.
35. Dewanjee S., et al. “Altered glucose metabolism in Alzheimer's disease: Role of mitochondrial dysfunction and oxidative stress”. Free Radical Biology and Medicine1 (2022): 134-157.
36. Gao X., et al. “Telomeres and mitochondrial metabolism: implications for cellular senescence and age-related diseases”. Stem Cell Reviews and Reports 18 (2022): 2315-2327.
37. Amorim JA., et al. “Mitochondrial and metabolic dysfunction in ageing and age-related diseases”. Nature Reviews Endocrinology 18 (2022): 243-258.
38. Leonardi R and Jackowski S. “Biosynthesis of pantothenic acid and coenzyme A”. Coenzymes, cofactors and Prosthetic Groups 2.2 (2007).
39. Turunen M., et al. “Metabolism and function of coenzyme Q”. Biochimica et Biophysica Acta (BBA) - Biomembranes1-2 (2004): 171-199.
40. Bonora M., et al. “ATP synthesis and storage”. Purinergic Signal3 (2012): 343-357.
41. Sun Q., et al. “Heavy metals induced mitochondrial dysfunction in animals: Molecular mechanism of toxicity”. Toxicology 469 (2022): 153136.
42. ElKhatib MAW., et al. “Effect of inflammation on cytochrome P450-mediated arachidonic acid metabolism and the consequences on cardiac hypertrophy”. Drug Metabolism Reviews1-2 (2023): 50-74.
43. Liu T., et al. “NF-κB signaling in inflammation”. Signal Transduction and Targeted Therapy 2 (2017): 17023.
44. Cargnello M and Roux PP. “Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases”. Microbiology and Molecular Biology Reviews 1 (2011): 50-83.
45. Cannino G., et al. “Cadmium and mitochondria”. Mitochondrion6 (2009): 377-384.
46. Bailey SM. “Chapter 89 - Role of oxidative stress in alcohol-induced mitochondrial dysfunction”. In: Comprehensive Handbook of Alcohol Related Pathology, Eds: Victor R. Preedy, Ronald Ross Watson, Academic Press, 31 (2005): 1153-1173.
47. Hales KG. “Mitochondrial fusion and division”. Nature Education9 (2010): 12.
48. Pizzorno J. “Mitochondria-fundamental to life and health”. Integrative Medicine (Encinitas) 2 (2014): 8-15.
49. Browning JD and Horton JD. “Molecular mediators of hepatic steatosis and liver injury”. Journal of Clinical Investigation 2 (2004): 147-152.
50. Grattagliano I., et al. “Mitochondria in chronic liver disease”. Current Drug Targets 6 (2011): 879-893.
51. Morio B., et al. “Role of mitochondria in liver metabolic health and diseases”. Cell Calcium 94 (2021): 102336.
52. Longo N., et al. “Carnitine transport and fatty acid oxidation”. Biochimica et Biophysica Acta (BBA) 10 (2016): 2422-2435.
53. Farrell GC and Larter CZ. “Liver failure and liver disease. Nonalcoholic fatty liver disease: From steatosis to cirrhosis. Hepatology”. Liver Failure and Liver DiseaseS1 (2006): S99-S112.
54. Fasano A. “All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases”. F1000Research 9 (2020): F1000 Faculty Rev-69.
55. Campbell AW and Weinstock LB. “Molds, mycotoxins, the brain, the gut and misconceptions”. Alternative Therapies in Health and Medicine3 (2022): 8-12.
56. Kiani H., et al. “Distribution and risk factors associated with intestinal parasite infections among children with gastrointestinal disorders”. Gastroenterology and Hepatology from Bed to Bench1 (2016): S80-S87.
57. Merck Manual, Consumer version (2023).
58. Lim S. “Metabolic acidosis”. Acta Medica Indonesiana 3 (2007): 145-150.
59. Xu C., et al. “Induction of Phase I, II and III Drug Metabolism/Transport by Xenobiotics”. Archives of Pharmacal Research 3 (2005): 249-268.
60. Krishna S., et al. “Artemisinins: their growing importance in medicine”. Trends in Pharmacological Sciences 10 (2008): 520-527.
61. Beshay EVN. “Therapeutic efficacy of Artemisia absinthium against Hymenolepis nana: in vitro and in vivo studies in comparison with the anthelmintic praziquantel”. Journal of Helminthology 3 (2018): 298-308.
62. Rao R and Samak G. “Role of glutamine in protection of intestinal epithelial tight junctions”. Journal of Epithelial Biology and Pharmacology Suppl 1-M7 (2012): 47-54.
63. Camilleri M. “Leaky gut: mechanisms, measurement and clinical implications in humans”. Gut 8 (2019): 1516-1526.
64. Camilleri M and Vella A. “What to do about the leaky gut”. Gut 2 (2022): 424-435.
65. de Carvalho CCCR and Caramujo MJ. “The various roles of fatty acids”. Molecules10 (2018): 2583.
66. Alpha-Lipoic acid, NIH (2023).
67. Tenório MCDS., et al. “N-Acetylcysteine (NAC): Impacts on human health”. Antioxidants (Basel) 6 (2021): 967.
68. Rushworth GF and Megson IL. “Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits”. Pharmacology and Therapeutics2 (2014): 150-159.
69. Kopytko P., et al. “Garcinol - A natural histone acetyltransferase inhibitor and new anti-cancer epigenetic drug”. International Journal of Molecular Sciences 6 (2021): 2828.
70. Aggarwal V., et al. “Garcinol exhibits anti-neoplastic effects by targeting diverse oncogenic factors in tumor cells”. Biomedicines5 (2020): 103.
71. Ghosh J and Sil PC. “Arjunolic acid: A new multifunctional therapeutic promise of alternative medicine”. Biochimie 6 (2013): 1098-1109.
72. Rabelo ACS and Costa DC. “A review of biological and pharmacological activities of Baccharis trimera”. Chemico-Biological Interactions 296 (2018): 65-75.
73. Amaral EC., et al. “Efectos cardioprotectores de Baccharis trimera (Less.) DC en un modelo de roedor de exposición a narguile, alcohol y bebidas energéticas”. Boletín Latinoamericano Y Del Caribe De Plantas Medicinales Y Aromáticas3 (2022): 377-392.
74. Carlisle AE., et al. “Selenium detoxification is required for cancer-cell survival”. Nature Metabolism 2 (2020): 603-611.
75. Jyotirmayee B and Mahalik G. “A review on selected pharmacological activities of Curcuma longa L”. International Journal of Food Properties 1 (2022): 1377-1398.
76. Fuloria S., et al. “A comprehensive review on the therapeutic potential of Curcuma longa in relation to its major active constituent curcumin”. Frontiers in Pharmacology 13 (2022): e820806.
77. Saji R., et al. “Turmeronols (A and B) from Curcuma longa have anti-inflammatory effects in lipopolysaccharide-stimulated BV-2 microglial cells by reducing NF-κB signaling”. Bioscience of Microbiota, Food and Health3 (2023): 172-179.
78. Rothhammer V and Quintana FJ. “The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease”. Nature Reviews Immunology 19 (2019): 184-197.
79. Alrawaiq NS and Abdullah A. “A review of antioxidant polyphenol curcumin and its role in detoxification”. International Journal of PharmTech Research 1 (2014): 280-289.
80. Toden S and Goel A. “The holy grail of curcumin and its efficacy in various diseases: is bioavailability truly a big concern?” Journal of Restorative Medicine 1 (2017): 27-36.
81. Bansal SS., et al. “Advanced drug delivery systems of curcumin for cancer chemoprevention”. Cancer Prevention Research (Phila)8 (2011): 1158-1171.
82. Kumar D., et al. “Enhanced bioavailability and relative distribution of free (unconjugated) curcuminoids following the oral administration of a food-grade formulation with fenugreek dietary fibre: A randomised double-blind crossover study”. Journal of Functional Foods 22 (2016): 578-587.
83. Matthewman C., et al. “Review: Bioavailability and efficacy of "free" curcuminoids from CurcumaGalactoMannoside (CGM) curcumin formulation”. Nutrition Research Review (2023): 1-18.
84. Suruse PB., et al. “Development of microcapsules of glimepiride using fenugreek seed extract”. International Journal of Pharmaceutical and Phytopharmacological Research (elJPPR)3 (2013): 212-215.
85. Abdi G., et al. “Medicinal herbs as a functional food for health”. In: Functional foods. Eds: Sajad Ahmad Wani, Mohamed S. Elshikh, Mona S. Al-Wahaibi, Haroon Rashid Naik. CRC Press, USA (2023).
86. Krishnakumar I., et al. “Improved blood-brain-barrier permeability and tissue distribution following the oral administration of a food-grade formulation of curcumin with fenugreek fibre”. Journal of Functional Foods 14 (2015): 215-225.
87. Gillessen A and Schmidt HH-J. “Silymarin as supportive treatment in liver diseases: A narrative review”. Advances in Therapy 37 (2020): 1279-1301.
88. Avelar CR., et al. “Effect of silymarin on biochemical indicators in patients with liver disease: Systematic review with meta-analysis”. World Journal of Gastroenterology 27 (2017): 5004-5017.
89. Akhtar MN., et al. “Silymarin: a review on paving the way towards promising pharmacological agent”. International Journal of Food Properties1 (2023): 2256-2272.
90. Ezzat MI., et al. “In-depth hepatoprotective mechanistic study of Phyllanthus niruri: In vitro and in vivo studies and its chemical characterization”. PLoS ONE1 (2020): e0226185.
91. Ramya V., et al. “Unlocking the power of Phyllanthus niruri - Nature's hidden gem”. Chronicle of Bioresource Management4 (2023): 085-087.
92. Bagalkotkar G., et al. “Phytochemicals from Phyllanthus niruri and their pharmacological properties: a review”. Journal of Pharmacy and Pharmacology 58 (2006): 1559-1570.
93. Guan Y-S and He Q. “Plants consumption and liver health”. Evidence-Based Complementary and Alternative Medicine (2015): 824185.
94. Fine AM. “Oligomeric proanthocyanidin complexes: history, structure, and phytopharmaceutical applications”. Alternative Medicine Review: A Journal of Clinical Therapeutic2 (2000): 144-151.
95. Xu Z., et al. “Proanthocyanidins: Oligomeric structures with unique biochemical properties and great therapeutic promise”. Natural Product Communications3 (2012).
96. Demirkol O and Cagri-Mehmetoglu A. “Biologically important thiols in various organically and conventionally grown vegetables”. Journal of Food and Nutrition Research2 (2008): 77-84.
97. Ferreira D and Slade D. “Oligomeric proanthocyanidins: naturally occurring O-heterocycles”. Natural Product Reports 19 (2002): 517-541.
98. Arenas-Jal M., et al. “Coenzyme Q10 supplementation: Efficacy, safety, and formulation challenges”. Comprehensive Reviews in Food Science and Food Safety2 (2020): 574-594.
99. Demirkol O., et al. “Biologically important thiols in various vegetables and fruits”. Journal of Agricultural and Food Chemistry26 (2004): 8151-8154.
100. Carson JF. “Chemistry and biological properties of onions and garlic”. Food Reviews International1-2 (1987): 71-103.
101. Nicastro HL., et al. “Garlic and onions: Their cancer prevention properties”. Cancer Prevention Research (Phila)3 (2015): 181-189.
102. Ulrich K and Jakob U. “The role of thiols in antioxidant systems”. Free Radical Biology and Medicine 140 (2019): 14-27.
103. Vašák M and Hasler DW. “Metallothionein’s: new functional and structural insights”. Current Opinion in Chemical Biology2 (2000): 177-183.
104. Coleman JE. “Zinc proteins: Enzymes, storage, proteins, transcription factor, and replication proteins”. Annual Review of Biochemistry 61 (1992): 897-946.
105. Thompson MW. “Regulation of zinc-dependent enzymes by metal carrier proteins”. Biometals 35 (2022): 187-213.
106. De LC and De T. “Nutrient rich foods in human diet as immunity boosters”. Journal of Pharmacognosy and Phytochemistry 3 (2021): 197-206.
107. Noulas C., et al. “Zinc in soils, water and food crops”. Journal of Trace Elements in Medicine and Biology 49 (2018): 252-260.
108. Lindsay WL. “Zinc in soils and plant nutrition”. In: Advances in Agronomy, Ed: Brady NC, Academic Press, Volume 24 (1972): 147-186.
109. Allocati N., et al. “Glutathione transferases: substrates, inhibitors and pro-drugs in cancer and neurodegenerative diseases”. Oncogenesis 7 (2018): 8.
110. Hayes PC., et al. “Glutathione S-transferase in humans in health and disease”. Gut7 (1991): 813-818.
111. Vaish S., et al. “Glutathione S-transferase: a versatile protein family”. 3 Biotech 10 (2020): 321.
112. Hayes JD and Strange RC. “Glutathione S-transferase polymorphisms and their biological consequences”. Pharmacology3 (2000): 154-166.
113. Strange RC., et al. “Glutathione S-transferase: genetics and role in toxicology”. Toxicology Letters 112-113 (2000): 357-363.
114. Huber WW., et al. “Potential chemoprotective effects of the coffee components kahweol and cafestol palmitates via modification of hepatic N-acetyltransferase and glutathione S-transferase activities”. Environmental and Molecular Mutagenesis 4 (2004): 265-276.
115. Rowland A., et al. “The UDP-glucuronosyltransferases: Their role in drug metabolism and detoxification”. The International Journal of Biochemistry and Cell Biology6 (2013): 1121-1132.
116. Ha CE and Bhagavan NV. “Carbohydrate metabolism II: gluconeogenesis, glycogen synthesis and breakdown, and pentose phosphate pathway”. Chap 13, Eds: Chung Eun Ha, N.V. Bhagavan, Essentials of Medical Biochemistry (Third Edition), Academic Press (2023): 249-275.
117. Ouzzine M., et al. “The UDP-glucuronosyltransferases of the blood-brain barrier: their role in drug metabolism and detoxication”. Frontiers in Cellular Neuroscience 8 (2014): e00349.
118. Applequist WL and Moerman DE. “Yarrow (Achillea millefolium): A neglected panacea? A review of ethnobotany, bioactivity, and biomedical research”. Economic Botany 65 (2011): 209-225.
119. Akram M. “Minireview on Achillea millefolium Linn”. Journal of Membrane Biology 246 (2013): 661-663.
120. Ritika Rizwana., et al. “Achillea millefolium, common yarrow”. In: Sharma, A., Nayik, G.A. (eds) Immunity Boosting Medicinal Plants of the Western Himalayas. Springer, Singapore (2023).
121. Al Amrani HA and Aneed IK. "Artichoke and health (food and medicine): A review". Journal of Genetic and Environmental Resources Conservation2 (2023): 114-124.
122. Xia Y., et al. “Effects of cumin, coriander, and sichuan pepper on microbiota and the antioxidant capacities of human faecal cultures”. Food and Humanity 1 (2023): 1091-1098.
123. Zandi M., et al. “Improved yields and essential oil composition of ajowan (Trachyspermum ammi) and soil fertility properties in intercropping systems”. Biological Agriculture and Horticulture 39.1 (2023): 1-18.
124. Spence C. “Ginger: The pungent spice”. International Journal of Gastronomy and Food Science 33 (2023): 100793.
125. Philips CA., et al. “A single-center experience on outcomes of complementary and alternative medicine use among patients with cirrhosis”. Hepatology Communications7 (2019): 1001-1012.