Nutrient Support for Detoxification

Nutrient Support for Detoxification

Every day the human body is exposed to toxic compounds in the air, water and food. An individual’s ability to detoxify these substances, both from exogenous sources, such as heavy metals, xenobiotics, chemical pollutants, and processed foods, and endogenous sources, such as the by-products of metabolism, is critical to overall health.

Several organ systems work together as part of a comprehensive network to aid the breakdown and elimination of toxins. While the liver is considered the primary detoxification organ, the gastrointestinal tract also plays a significant role. The kidneys, skin and lungs are also involved.

Despite the body’s innate ability to detox, the body can get into a state of toxic overload, or oxidative stress, which occurs when the amount of toxic exposure surpasses the body’s ability to detoxify. Furthermore, poor diet, nutrient status and lifestyle can diminish endogenous antioxidant and detoxification systems reducing resilience. When this happens, studies have shown that inflammation and chronic diseases such as cancer (Cohen & Jefferies, 2019;  Wan et al., 2022), cardiovascular disease (Pizzorno, 2022), diabetes (Tremblay and Hamet et al., 2019), autoimmune diseases (Miller et al., 2012); Parkinson’s disease (Nandipati et al., 2016) and Alzheimer’s disease can result (Vegas-Suárez et al., 2022).

Reducing exposure is key to optimising health and wellbeing; however, removing all sources of environmental toxins is impossible. Therefore, supporting liver detoxification, antioxidant systems and gut function through nutritional and lifestyle strategies is necessary to minimise toxic burden and maximise health and wellbeing.

Toxic burden

There are no safe levels of toxins, and every day we are exposed to environmental toxins, medications, and toxins from personal care products, clothing, food packaging, food, air and water. There are many environmental toxins, including endocrine-disrupting chemicals, heavy metals, EMFs, fluorinated chemicals, solvents, pesticides and flame retardants. Over time our exposure to environmental toxins can exceed our ability to metabolise and detoxify them, which can lead to chronic disease (Gibson, 2017). As a result, environmental toxicities have become one of the most significant global health burdens. In 2012, the World Health Organisation estimated that 12.6 million deaths every year were attributed to our unhealthy environments via chemical exposures and air, soil and water pollution (World Health Organisation, 2016).

Heavy metals can be toxic at low doses and cause toxicity in specific organs of the human body, such as nephrotoxicity, neurotoxicity, hepatotoxicity, skin toxicity, and cardiovascular toxicity. Many heavy metals are classified as carcinogens (Mitra et al., 2022). The cumulative burden of heavy metals is known to result in more significant toxicity to the body and contribute to liver injury, decreased antioxidant activity, neurotransmitter alterations, cardiovascular disease and kidney necrosis (Monaco et al., 2021; Singh et al., 2017).

 

Detoxification pathways

Liver detoxification is a three-phase process essential for the removal of drugs and toxins from the body:

Phase 1 utilises the cytochrome P450 family of enzymes to transform lipid-soluble compounds into intermediate metabolites in preparation for Phase II. This is achieved through chemical reactions (oxidation, reduction, hydrolysis).

Phase II (conjugation pathway) converts drugs, hormones, intermediate metabolites, and toxins into water-soluble, more easily excretable substances. Phase II reactions involve the addition of a small polar molecule to the substance (e.g. cysteine, glycine or a sulphur molecule), a conjugation step that may or may not be preceded by Phase I (Cline et al., 2015).

Phase III (antiporter phase) is the final step of the detoxification process in the body. It is carried by transport proteins to eliminate toxins and metabolic products from cells and, eventually, the body. Water-soluble substances go to the kidneys to be eliminated in the urine, and fat-soluble substances are packaged into bile and eliminated via the stool (Liska et al., 1998).

The rate at which phase I produces intermediate metabolites must be balanced by the rate at which phase II conjugates these intermediates for effective toxin elimination. The intermediate metabolites produced in phase I are often more toxic than the original compound. If these activated intermediate metabolites are not metabolised via phase II conjugation pathways, they can result in elevated free radicals and the potential for secondary tissue damage. Furthermore, excessive amounts of toxic chemicals such as pesticides and dioxins can disrupt the P450 enzyme system, causing overactivity of this pathway (this is referred to as induction) and the production of damaging free radicals.

If the phase I and II pathways become overloaded or have impaired functioning, there will be a build-up of toxins or free radicals in the body. High phase I and low phase II activity can result in excessive free radical production and increased oxidative load. In addition, low phase I and high phase II can delay the clearance of toxins from the system.

Many toxins are fat soluble and accumulate in fatty tissues, where they may persist for years or even a lifetime. The brain and the endocrine glands are fatty organs and common sites for accumulating fat-soluble toxins. This may result in metabolic disorders (Le Magueresse-Battistoni et al., 2018), cognitive impairment (Sarailoo et al., 2022; Suresh et al., 2022), hormonal imbalances (Rutkowska et al., 2016), infertility (Pizzorno, 2018), menstrual irregularities (Hammer et al., 2020), adrenal gland exhaustion (Alexandraki et al., 2022), and thyroid dysfunction (Babić Leko et al., 2021). Many of these chemicals are carcinogenic and have been implicated in the rising incidence of many cancers (Bokobza et al., 2021; Macedo et al., 2022).

 

Nutrients for Phases

Various macronutrients and micronutrients are required to ensure all three phases of liver detoxification are working optimally and reduce the risk of free radical damage produced during the detoxification process.

Phase I

The nutritional cofactors of P450 phase I detoxification include riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), folate (5-MTHF), vitamin B12, magnesium, branched-chain amino acids (leucine, isoleucine, valine), and phospholipids (Liska, 1998). Deficiencies in minerals such as zinc, copper, magnesium and molybdenum may decrease the activity of the cytochrome P450 enzyme system (Anderson & Kappas, 1991).

 

Phase II

Many nutrients are required for phase II pathways to function correctly and remain balanced with phase I detoxification. Conjugating substances for phase II include taurine, glycine, sulfate, ornithine, glucuronic acid and glutamine. Phase II reactions depend on adequate levels of these nutrients and enzymatic cofactors (Satsu, 2019). If necessary nutrients are in low supply, phase II reactions cannot remain in equilibrium with phase I reactions. Essential cofactors include vitamins B2, B3, B6, B12, and folate (Liska, 1998). In addition, sulforaphane (SFN), a sulfur-rich compound in cruciferous vegetables (e.g. broccoli sprouts), increases antioxidant and detoxification activity in the body via phase II enzyme induction and Nrf2 activation (Fahey & Talalay. 1999; Vargas-Mendoza et al., 2021).

 

Phase III

Phase III transport proteins are concentrated in hepatocytes (where they pump compounds into bile) and renal cells of the proximal tubules (where they pump compounds into the urine). They are also concentrated in the intestinal epithelium (Shen & Kong, 2009). Therefore nutrients supporting bile production and flow and gastrointestinal health can support the elimination of toxins from the body. Glutamine, prebiotics and probiotics can improve healthy intestinal barrier function along with phase III transporter proteins in the intestinal wall.

 

Supporting detoxification

 

Antioxidants

Toxins can produce reactive oxygen species, which can cause oxidative damage to DNA and membrane lipids. Therefore, enhancing endogenous antioxidant systems and providing exogenous antioxidant compounds may assist liver detoxification by quenching free radicals produced during detoxification (Percival, 1997). Two of the primary endogenous antioxidants are glutathione and superoxide dismutase.

Glutathione, produced from cysteine, glycine and glutamine, is the body’s most potent intracellular antioxidant system, protecting cells from free radicals and toxic chemicals. It also plays a crucial role in liver detoxification, providing one of the most important functional groups required for phase II conjugation (Kaplowitz, 1981). Glutathione also works alongside metallothioneins in the detoxification and removal of heavy metals. In addition to the amino acids, vitamin C and selenium can increase glutathione levels (Gerard-Monnier & Chaudiere, 1996).

Superoxide dismutases (SODs) are antioxidant enzymes found in all human body cells. They break down superoxide radicals, which are toxic to living cells and cause DNA mutations, into harmless components of oxygen and hydrogen peroxide. There are two copper-zinc-containing SODs and one manganese-containing SOD, and adequate levels of these trace minerals are required for the formation and activity of these enzymes. Conversely, heavy metals, including cadmium and lead, have been shown to decrease the levels and activity of SOD (Ogunrinola et al., 2016; Patil et al., 2006).

 

Aside from eating antioxidant-rich food such as fruits and vegetables, taking quality antioxidant supplements is one way to protect the body from toxicity. Key antioxidants include:

Vitamin C: Vitamin C is the body’s primary water-soluble antioxidant. Present in blood, body fluids, and inside all cells, it protects against free radical damage. It helps reprocess glutathione by converting oxidised glutathione back to its active form. Vitamin C is a powerful antioxidant that plays an important role in detoxification, including metabolising and eliminating heavy metals (Jan et al., 2015).

Vitamin E: As an antioxidant, vitamin E works via the fat-soluble pathways involving liver detoxification. It may also assist in heavy metal detoxification as it is antagonistic to the heavy metals mercury and arsenic (Argawal et al., 2010; Qureshi et al., 2009).

Selenium: Selenium is a component of selenoproteins and enzymes such as glutathione peroxidase. These have antioxidant properties that help to break down peroxides, which can damage tissues and DNA, leading to inflammation and chronic disease (Kiełczykowska et al., 2018).

Zinc: Zinc acts as a co-factor for important enzymes, including superoxide dismutase, that contribute to the proper functioning of the antioxidant defence system. Zinc is a potent inducer of metallothioneins which are small proteins that can bind to heavy metals (Marrero et al., 2017).

Alpha lipoic acid: Alpha-lipoic acid (ALA) is an important intracellular antioxidant that regenerates other antioxidants (e.g. vitamin C and E) and has metal-chelating activity (e.g. iron, copper, manganese, zinc and mercury) (Bjørklund et al., 2019; Rochette et al., 2013). In addition, it enhances intra- and extracellular levels of glutathione, increasing heavy metal detoxification.

Bioflavonoids: Water soluble, bioflavonoid antioxidants are found in many fruit and plants. The antioxidant chemicals involved in these foods include anthocyanins, flavonoids, polyphenols, and coffeic acid, among others. Flavonoids can detoxify heavy metals by acting as natural chelators by binding to heavy metals. Flavonoid-metal chelate complexes have higher antioxidant activity than flavonoids alone, meaning they can further reduce oxidative stress (Symonowic et al., 2012).

Beta carotene and other carotenoids: Beta carotene and other carotenoids are major antioxidants found in fruit and vegetables. Beta-carotene is a potent fat-soluble antioxidant that acts synergistically with other antioxidants (e.g., E and C) (Braun & Cohen, 2007). One of the best-known sources of natural dietary beta-carotene and mixed carotenoids is Dunaliella salina, a marine phytoplankton (microalgae) (Pourkarimi et al., 2020).

 

Gastrointestinal health

The body’s ability to protect itself from toxic substances largely depends upon the gastrointestinal tract’s health (GIT). Intestinal epithelial cells (enterocytes) have a detoxification system, which serves as a chemical barrier in the gut (McKinnon et al., 1995). Approximately 25% of detoxification occurs in the GIT. Toxic xenobiotics are metabolised by phase I detoxification enzymes (CP450 enzymes), and the resultant less-harmful compounds are efficiently excreted from the cells by transport proteins (phase III), thus reducing the burden of un-metabolised xenobiotics in the internal environment (Roediger & Babidge, 1997).

The GIT also functions as an important physical barrier against exogenous harmful compounds, including pathogenic microorganisms and toxic chemicals. However, this barrier can become compromised due to inflammation of the gut lining, overgrowth or imbalance of intestinal flora, chronic nutritional insufficiency, and exposure to circulating bacterial toxins. Contributing factors include a highly refined diet, stress, medication use and exposure to allergens and toxins. Increased intestinal permeability (“leaky gut”) allows greater entry of toxins, pathogens and antigens (foreign proteins) into the body. The increased burden of toxic substances and pathogens can lead to inappropriate immune reactions and the development of disease (Di Tommaso et al., 2021; Farré et al., 2020).

Gut microbiota also play a key role in detoxification by neutralising potential carcinogens and toxic compounds; enhancing the excretion of toxins; modulating the expression of detoxification enzymes in the liver, and producing metabolites from the breakdown of xenobiotics, hormones and other toxins (Claus et al., 2016).

Pathogenic gut bacteria, such as Escherichia coli, Bacteroides species, and Clostridium perfringens, can produce the enzyme beta-glucuronidase (Skar & Skar, 1988). Beta-glucuronidase exerts a cleavage action on glucuronide metabolites, which reactivates and allows toxins to re-enter circulation. Unfortunately, this enzyme can also convert pro-carcinogens to carcinogenic compounds, and elevated beta-glucuronidase activity has been associated with certain cancers, such as pancreatic and breast (Sperker et al., 2000; Sui et al., 2021).

While heavy metals can disturb gut microbiota balance leading to dysbiosis, some beneficial gut bacteria can also assist detoxification processes by binding or sequestering toxicants such as heavy metals (e.g. lead, arsenic, mercury) and by enhancing enzymes for metabolising heavy metals (Bist & Choudhary, 2022) (Arun et al., 2021).

Therefore, supporting the gut microbiome is critical to both proper detoxification and overall health. Pre- and probiotics can help enhance detoxification by inhibiting the adhesion of toxins to intestinal cells, binding to and detoxifying toxic compounds by inhibiting their absorption and lowering their availability and stimulating intestinal peristalsis and faecal excretion. In addition, a healthy gut microbiome promoted via probiotic supplementation can also enhance gut barrier integrity, preventing toxins from entering circulation (Ghosh et al., 2020).

 

Bile production and enterohepatic circulation

The gallbladder plays a vital role in detoxification, and it is essential to support its function so that the body can effectively detoxify. Bile binds to fat-soluble toxins to carry them out of the body through our stools. Ninety-five percent of bile is reabsorbed at the end of small intestines by enterocytes and transported back to the liver through a process called enterohepatic circulation. Five percent of bile is excreted through the stools, removing toxins from the body. Impairment of bile flow (cholestasis) may result in a build-up of toxins within the body (Dawson, 2018).

Artichoke leaf extract (Cynara scolymus), dandelion root extract (Taraxacum officinale), and barberry (Berberis vulgaris) have traditionally been used to support healthy bile flow (Bone & Mills, 2018). Adequate levels of amino acids such as glycine and taurine are necessary, as these are essential in conjugating bile acids to bile salts (Trefflich et al., 2019). In addition, lipotropic nutrients, such as methionine, choline, folic acid and the vitamins B6 and B12, are useful for stimulating the flow of bile from the liver.

 

Natural chelators and binders

Chelating agents are organic or inorganic compounds capable of binding metal ions to form complex ring-like structures called ‘chelates’, which are readily excreted from the body (Sears, 2013). Binders are natural substances which hold or draw in toxins and aid removal from the body, such as fibre and pectin.

Metallothioneins are cysteine-rich, metal-binding proteins. They maintain homeostasis of essential minerals, such as copper and zinc, and protect against toxic metals, such as lead and cadmium, by binding them and scavenging free radicals generated by oxidative stress. Chromium can inhibit zinc-metallothionein expression, while zinc supplementation can restore metallothionein expression (Majumder et al., 2003). The role of zinc supplementation during the course of chelation of lead (Flora & Tandon, 1993) and cadmium (Matović et al., 2011) has been reported to have many beneficial effects.

Dietary fibre from grains and fruit can bind certain toxins. It can be used as an adjunct or alternative to chelation therapy to interrupt enterohepatic recirculation and modulate intestinal microbiota. Studies have shown that dietary fibre can improve biotransformation and elimination of toxins, including PCBs (Vermeylen et al., 2008), and heavy metals, including cadmium and mercury (Li et al., 2016; Rowland et al., 2016).

Pectin is an alternative to conventional chelators by binding heavy metals such as arsenic, lead, cadmium, and mercury and their excretion from the human body (Eliaz et al., 2006; Lara-Espinoza et al., 2018; Naqash et al., 2017).

 

Mineral antagonists

Mineral antagonists can be used to decrease or block the absorption or metabolic function of nutrients or heavy metals and therefore aid in excretion. For example, selenium may bind and enhance the secretion of heavy metals, including inorganic and methyl mercury, arsenic and cadmium (Berry et al., 2008; Zwolak et al., 2020). Calcium supplementation reduced lead mobilisation from maternal bones during pregnancy and lactation, protecting the newborn and infant (Sears, 2013). Magnesium and zinc can reduce cadmium absorption, and iron supplementation reduces lead accumulation in children (Sears, 2013).

A mineral deficiency may facilitate the absorption of a toxic metal and allow the toxic accumulation of another mineral. For example, lead toxicity can occur with insufficient calcium or iron intake. Likewise, cadmium can accumulate in the presence of marginal or deficient zinc (Matović et al., 2013). Therefore, mineral supplementation may be required to combat the effects of heavy metals and provide the precursors for the body’s natural defense systems.

HTMA and detoxification

Hair tissue mineral analysis (HTMA) is an important and very useful test for assessing antioxidant and detoxification requirements. As hair cells grow, they are exposed to the internal metabolic activity of the body. As the hair grows away from the internal environment of the skin’s dermal layer, the cells dry out, harden and lock in a record of this recent metabolic activity.

HTMA indicates nutritional mineral imbalances and has been shown to be an effective measure of heavy metal status. The presence of heavy metals in the body, such as lead, mercury, cadmium, arsenic, uranium, beryllium and aluminium, can increase free radical damage significantly. Hair mineral analysis can be used to assess disturbances to detoxification pathways (selenium, molybdenum and sulfur levels/ratios) and select appropriate minerals to antagonise and aid the elimination of heavy metals from the body. HTMA is also an excellent indicator of selenium and zinc status, crucial mineral antioxidants.

 

InterClinical Comment

Remember to join us for Mentoring on the following dates or at the one-day HTMA Practitioner Seminar to learn more about hair mineral analysis and nutrient requirements for detoxification.

Nutrient Support for Detoxification
Wednesday 29th June 2023 – 1PM AEDT

CASE STUDIES 1
Wednesday 5th July 2023 – 1PM AEDT

COMPLEX CASE STUDIES
Wednesday 12th July 2023 – 1PM AEDT

 

References

Agarwal R, Goel SK, Chandra R, Behari JR. Role of vitamin E in preventing acute mercury toxicity in rat. Environmental Toxicology and Pharmacology. 2010 Jan 1;29(1):70-8.

Alexandraki KI, Spyroglou A, Tucci L, Di Dalmazi G. Environmental Impact on the Hypothalamus–Pituitary–Adrenal Axis. InEnvironmental Endocrinology and Endocrine Disruptors: Endocrine and Endocrine-targeted Actions and Related Human Diseases 2022 Nov 17 (pp. 1-33). Cham: Springer International Publishing.

Anderson KE, Kappas A. Dietary regulation of cytochrome P450. Annual review of nutrition. 1991 Jul;11(1):141-67.

Arun KB, Madhavan A, Sindhu R, Emmanual S, Binod P, Pugazhendhi A, Sirohi R, Reshmy R, Awasthi MK, Gnansounou E, Pandey A. Probiotics and gut microbiome− Prospects and challenges in remediating heavy metal toxicity. Journal of Hazardous Materials. 2021 Oct 15;420:126676.

Babić Leko M, Gunjača I, Pleić N, Zemunik T. Environmental factors affecting thyroid-stimulating hormone and thyroid hormone levels. International Journal of Molecular Sciences. 2021 Jun 17;22(12):6521.

Berry MJ, Ralston NV. Mercury toxicity and the mitigating role of selenium. Ecohealth. 2008 Dec;5(4):456-9.

Bist P, Choudhary S. Impact of heavy metal toxicity on the gut microbiota and its relationship with metabolites and future probiotics strategy: a review. Biological Trace Element Research. 2022 Dec;200(12):5328-50.

Bjørklund G, Aaseth J, Crisponi G, Rahman MM, Chirumbolo S. Insights on alpha lipoic and dihydrolipoic acids as promising scavengers of oxidative stress and possible chelators in mercury toxicology. Journal of inorganic biochemistry. 2019 Jun 1;195:111-9.

Bokobza E, Hinault C, Tiroille V, Clavel S, Bost F, Chevalier N. The adipose tissue at the crosstalk between EDCs and cancer development. Frontiers in Endocrinology. 2021 Jul 20;12:691658.

Bone K, Mills S. Principles and practice of phytotherapy: modern herbal medicine. Elsevier Health Sciences; 2012 Dec 31.

Braun, L, Cohen, M, Beta Carotene Monograph, Herbs and natural Supplements, Elsevier, 2007, p164

Claus SP, Guillou H, Ellero-Simatos S. The gut microbiota: a major player in the toxicity of environmental pollutants? NPJ Biofilms Microbiomes. 2016 May 4;2:16003. doi: 10.1038/npjbiofilms.2016.3. Erratum in: NPJ Biofilms Microbiomes. 2017

Cohen L, Jefferies A. Environmental exposures and cancer: using the precautionary principle. Ecancermedicalscience. 2019 Apr 16;13:ed91.

Dawson PA. Bile formation and the enterohepatic circulation. Physiology of the gastrointestinal tract. 2018 Jan 1:931-56.

Di Tommaso N, Gasbarrini A, Ponziani FR. Intestinal barrier in human health and disease. International journal of environmental research and public health. 2021 Dec 6;18(23):12836.

Eliaz I, Hotchkiss AT, Fishman ML, Rode D. The effect of modified citrus pectin on urinary excretion of toxic elements. Phytother Res. 2006 Oct;20(10):859-64.

Fahey JW, Talalay P. Antioxidant functions of sulforaphane: a potent inducer of Phase II detoxication enzymes. Food and Chemical Toxicology. 1999 Oct;37(9):973-9.

Farré R, Fiorani M, Abdu Rahiman S, Matteoli G. Intestinal permeability, inflammation and the role of nutrients. Nutrients. 2020 Apr 23;12(4):1185.

Flora SJ, Tandon SK. Beneficial effects of zinc supplementation during chelation treatment of lead intoxication in rats. Toxicology. 1990 Nov 1;64(2):129-39.

Gerard-Monnier D, Chaudiere J. Metabolism and antioxidant function of glutathione. Pathologie-biologie. 1996 Jan 1;44(1):77-85.

Ghosh SS, Wang J, Yannie PJ, Ghosh S. Intestinal barrier dysfunction, LPS translocation, and disease development. Journal of the Endocrine Society. 2020 Feb;4(2):bvz039.

Gibson JM. Environmental Determinants of Health. Chronic Illness Care. 2017 Nov 7:451–67.

Hammer KC, Veiga A, Mahalingaiah S. Environmental toxicant exposure and menstrual cycle length. Current Opinion in Endocrinology, Diabetes, and Obesity. 2020 Dec;27(6):373.

Jan AT, Azam M, Siddiqui K, Ali A, Choi I, Haq QM. Heavy Metals and Human Health: Mechanistic Insight into Toxicity and Counter Defense System of Antioxidants. Int J Mol Sci. 2015 Dec 10;16(12):29592-630.

Kaplowitz NE. The importance and regulation of hepatic glutathione. The Yale journal of biology and medicine. 1981 Nov;54(6):497.

Kiełczykowska M, Kocot J, Paździor M, Musik I. Selenium-a fascinating antioxidant of protective properties. Adv. Clin. Exp. Med. 2018 Feb 1;27(2):245-55.

Lara-Espinoza C, Carvajal-Millán E, Balandrán-Quintana R, López-Franco Y, Rascón-Chu A. Pectin and pectin-based composite materials: Beyond food texture. Molecules. 2018 Apr 18;23(4):942.

Le Magueresse-Battistoni B, Vidal H, Naville D. Environmental Pollutants and Metabolic Disorders: The Multi-Exposure Scenario of Life. Front Endocrinol (Lausanne). 2018 Oct 2;9:582. doi: 10.3389/fendo.2018.00582.

Li Y, Liu K, Shen J, Liu Y. Wheat bran intake can attenuate chronic cadmium toxicity in mice gut microbiota. Food Funct. 2016 Aug 10;7(8):3524-30.

Liska DJ. The detoxification enzyme systems. Altern Med Rev. 1998 Jun 3;3(3):187-98.

Macedo S, Teixeira E, Gaspar TB, Boaventura P, Soares MA, Miranda-Alves L, Soares P. Endocrine-disrupting chemicals and endocrine neoplasia: A forty-year systematic review. Environmental Research. 2022 Nov 30:114869.

Majumder S, Ghoshal K, Summers D, Bai S, Datta J, Jacob ST. Chromium (VI) down-regulates heavy metal-induced metallothionein gene transcription by modifying transactivation potential of the key transcription factor, metal-responsive transcription factor 1. Journal of Biological Chemistry. 2003 Jul 11;278(28):26216-26.

Marreiro DD, Cruz KJ, Morais JB, Beserra JB, Severo JS, De Oliveira AR. Zinc and oxidative stress: current mechanisms. Antioxidants. 2017 Jun;6(2):24.

Matović V, Buha A, Bulat Z, Đukić-Ćosić D. Cadmium toxicity revisited: focus on oxidative stress induction and interactions with zinc and magnesium. Arhiv za higijenu rada i toksikologiju. 2011 Mar 16;62(1):65-75.

McKinnon RA, Burgess WM, Hall PD, Roberts-Thomson SJ, Gonzalez FJ, McManus ME. Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues. Gut. 1995 Feb 1;36(2):259-67.

Miller FW, Alfredsson L, Costenbader KH, Kamen DL, Nelson LM, Norris JM, De Roos AJ. Epidemiology of environmental exposures and human autoimmune diseases: findings from a National Institute of Environmental Health Sciences Expert Panel Workshop. Journal of autoimmunity. 2012 Dec 1;39(4):259-71.

Mitra S, Chakraborty AJ, Tareq AM, Emran TB, Nainu F, Khusro A, Idris AM, Khandaker MU, Osman H, Alhumaydhi FA, Simal-Gandara J. Impact of heavy metals on the environment and human health: Novel therapeutic insights to counter the toxicity. Journal of King Saud University-Science. 2022 Jan 29:101865

Monaco A, Lacalamita A, Amoroso N, D’Orta A, Del Buono A, di Tuoro F, Tangaro S, Galeandro AI, Bellotti R. Random forests highlight the combined effect of environmental heavy metals exposure and genetic damages for cardiovascular diseases. Applied Sciences. 2021 Sep 10;11(18):8405.

Nandipati S, Litvan I. Environmental exposures and Parkinson’s disease. International journal of environmental research and public health. 2016 Sep;13(9):881.

Naqash F, Masoodi FA, Rather SA, Wani SM, Gani A. Emerging concepts in the nutraceutical and functional properties of pectin—A Review. Carbohydrate polymers. 2017 Jul 15;168:227-39.

Ogunrinola OO, Wusu DA, Fajana OO, Olaitan SN, Smith ZO, Bolaji AR. Effect of low level cadmium exposure on superoxide dismutase activity in rat. Tropical Journal of Pharmaceutical Research. 2016 May 11;15(1):115-9.

Patil AJ, Bhagwat VR, Patil JA, Dongre NN, Ambekar JG, Jailkhani R, Das KK. Effect of lead (Pb) exposure on the activity of superoxide dismutase and catalase in battery manufacturing workers (BMW) of Western Maharashtra (India) with reference to heme biosynthesis. Int J Environ Res Public Health. 2006 Dec;3(4):329-37.

Percival M. Nutritional support for detoxification. Applied Nutritional Science Report. 1997;23:1-5.

Pizzorno J. Environmental Toxins and Cardiovascular Disease. InNutritional and Integrative Strategies in Cardiovascular Medicine 2022 Apr 17 (pp. 281-291). CRC Press.

Pizzorno J. Environmental Toxins and Infertility. Integr Med (Encinitas). 2018 Apr;17(2):8-11.

Pourkarimi S, Hallajisani A, Alizadehdakhel A, Nouralishahi A, Golzary A. Factors affecting production of beta-carotene from Dunaliella salina microalgae. Biocatalysis and Agricultural Biotechnology. 2020 Oct 1;29:101771.

Qureshi F, Tahir M, Sami W. Protective role of vitamin C and E against sodium arsenate induced changes in developing kidney of albino mice. Journal of Ayub Medical College, Abbottabad: JAMC. 2009 Oct 1;21(4):63-9.

Rochette L, Ghibu S, Richard C, Zeller M, Cottin Y, Vergely C. Direct and indirect antioxidant properties of α‐lipoic acid and therapeutic potential. Molecular nutrition & food research. 2013 Jan;57(1):114-25.

Roediger WE, Babidge W. Human colonocyte detoxification. Gut. 1997 Dec 1;41(6):731-4.

Rowland IR, Mallett AK, Flynn J, Hargreaves RJ. The effect of various dietary fibres on tissue concentration and chemical form of mercury after methylmercury exposure in mice. Arch Toxicol. 1986 Jul;59(2):94-8.

Rutkowska AZ, Diamanti-Kandarakis E. Polycystic ovary syndrome and environmental toxins. Fertility and sterility. 2016 Sep 15;106(4):948-58.

Sarailoo M, Afshari S, Asghariazar V, Safarzadeh E, Dadkhah M. Cognitive impairment and neurodegenerative diseases development associated with organophosphate pesticides exposure: a review study. Neurotoxicity research. 2022 Oct;40(5):1624-43.

Satsu H. Regulation of detoxification enzymes by food components in intestinal epithelial cells. Food Science and Technology Research. 2019;25(2):149-56.

Sears ME. Chelation: harnessing and enhancing heavy metal detoxification–a review. ScientificWorldJournal. 2013 Apr 18;2013:219840.

Shen G, Kong AN. Nrf2 plays an important role in coordinated regulation of Phase II drug metabolism enzymes and Phase III drug transporters. Biopharmaceutics & drug disposition. 2009 Oct;30(7):345-55.

Singh N, Gupta VK, Kumar A, Sharma B. Synergistic effects of heavy metals and pesticides in living systems. Frontiers in chemistry. 2017 Oct 11;5:70.

Skar V, Skar AG, Strømme JH. Beta-glucuronidase activity related to bacterial growth in common bile duct bile in gallstone patients. Scand J Gastroenterol. 1988 Jan;23(1):83-90.

Sperker B, Werner U, Mürdter TE, Tekkaya C, Fritz P, Wacke R, Adam U, Gerken M, Drewelow B, Kroemer HK. Expression and function of β-glucuronidase in pancreatic cancer: potential role in drug targeting. Naunyn-Schmiedeberg’s archives of pharmacology. 2000 Aug;362:110-5.

Sui Y, Wu J, Chen J. The role of gut microbial β-glucuronidase in estrogen reactivation and breast cancer. Frontiers in cell and developmental biology. 2021 Aug 12;9:631552.

Suresh S, Singh A, Vellapandian C. Bisphenol A exposure links to exacerbation of memory and cognitive impairment: A systematic review of the literature. Neuroscience & Biobehavioral Reviews. 2022 Nov 1:104939.

Symonowicz M, Kolanek M. Flavonoids and their properties to form chelate complexes. Chemistry. 2012.

Trefflich I, Marschall HU, Giuseppe RD, Ståhlman M, Michalsen A, Lampen A, Abraham K, Weikert C. Associations between Dietary Patterns and Bile Acids-Results from a Cross-Sectional Study in Vegans and Omnivores. Nutrients. 2019 Dec 23;12(1):47.

Tremblay J, Hamet P. Environmental and genetic contributions to diabetes. Metabolism. 2019 Nov 1;100:153952.

Vargas-Mendoza N, Sandoval-Gallegos EM, Madrigal-Santillán EO, Morales-Martínez M, Soriano-

Ursúa MA, Angeles-Valencia M, Morales-González Á, Portillo-Reyes J, Morales-González JA. The cytoprotective activity of Nrf2 is regulated by phytochemicals (sulforaphane, curcumin, and silymarin). InPlant Antioxidants and Health 2021 Dec 18 (pp. 1-52). Cham: Springer International Publishing.

Vegas-Suárez S, Simón J, Martínez-Chantar ML, Moratalla R. Metabolic Diffusion in Neuropathologies: The Relevance of Brain-Liver Axis. Frontiers in physiology. 2022:929.

Vermeylen W, De Vos S, De Schrijver R. Effects of dietary wheat bran on absorption and accumulation of PCBs in rats. Chemosphere. 2008 Mar;71(2):277-83

Wan ML, Co VA, El-Nezami H. Endocrine disrupting chemicals and breast cancer: a systematic review of epidemiological studies. Critical Reviews in Food Science and Nutrition. 2022 Aug 29;62(24):6549-76

World Health Organisation. An estimated 12.6million deaths each year are attributable to unhealthy environments. [Internet]; 2016. [cited March 9, 2023].

Zwolak I. The Role of Selenium in Arsenic and Cadmium Toxicity: an Updated Review of Scientific Literature. Biol Trace Elem Res. 2020 Jan;193(1):44-63.