The Liver: Supportive Nutrients in Detoxification

The liver is a vital organ responsible for numerous essential metabolic and physiological functions, including detoxification. This process involves the elimination of cellular debris, medications, environmental toxicants, and mycotoxins through a series of well-coordinated phases: Phase I, Phase II, and Phase III. The primary role of liver detoxification is to transform lipophilic substances into more hydrophilic forms to facilitate their elimination from the body, as covered in The Liver: It’s Important Role in Detoxification blog. Substances such as those detected on our TOXDetect Profile for environmental toxicants and our MycoTOX Profile for mycotoxins range in their lipophilicity and undergo this transformation. 

This review explores various nutrients and plant derivatives that support the biochemical reactions facilitated by specific enzymes in each detoxification phase, promoting overall health of not just the liver, but the whole body as well. You will find an easy-to-follow table categorizing the nutrients into Vitamins, Minerals, Key Liver Support Nutrients, Bioflavonoids & Polyphenols, and Amino Acids with detailed explanations in the following sections. 

Key Supportive Nutrients of Liver Detoxification

When considering supplements and nutrients that support the intrinsic processes of liver detoxification, it is evident that many of these nutrients often have multiple roles rather than a singular function. They contribute to various aspects of liver detoxification – including enhancing the liver’s enzymatic reactions, protecting against oxidative stress due to the generation of reactive oxygen species, promoting efficient excretion of toxic substances, and supporting liver cell health and regeneration.  

Vitamins

B-Vitamins

B vitamins, particularly B2 (riboflavin), B3 (niacin), B6 (pyridoxine), B9 (folate), and B12 (cobalamin), are essential cofactors for the cytochrome P450 enzymes.⁵¹ 

Vitamin B6 helps in the conversion of homocysteine to cysteine (a precursor for glutathione synthesis) and been shown to protect hepatocytes from oxidative damage by reducing lipid peroxidation, protein oxidation, and DNA damage.⁵²  

Vitamin B12 (cobalamin) and folate (vitamin B9) are critical for the synthesis of S-adenosylmethionine (SAMe). SAMe is a key methyl donor in numerous methylation reactions that take place in phase II and supports glutathione levels.⁵³ 

Vitamin C  

Vitamin C (ascorbic acid) is a potent antioxidant that neutralizes reactive oxygen species (ROS) and oxidative stress in hepatocytes. Some evidence suggests that vitamin C supplementation can lower markers of oxidative stress, such as malondialdehyde (MDA), and increase antioxidant enzyme activities, including superoxide dismutase (SOD) and catalase (CAT).^{54 55}  

Vitamin C supports phase II by maintaining adequate levels of glutathione, which is critical for maintaining conjugation reactions.⁵⁶ It may also exert inflammation-modulation effects by modulating cytokine production and mitigating hepatic injury.⁵⁷ 

Vitamin E

Vitamin E, particularly in the form of α-tocopherol, also neutralizes ROS and helps to prevent oxidative damage to hepatocytes.⁵⁸ In phase II detoxification, vitamin E influences the activity of glutathione-dependent enzymes, such as glutathione-S-transferases (GSTs).⁵⁹ Lastly, vitamin E can mitigate potential liver damage induced by various xenobiotics, such as carbon tetrachloride and organophosphate pesticides, due to its ability to reduce lipid peroxidation and maintain cellular integrity.⁶⁰  

Minerals 

Essential minerals such as magnesium, zinc, and selenium are important for the proper functioning of detoxification enzymes by serving as cofactors for the different reactions in the various phases of liver detoxification.⁶¹ 

Zinc 

Zinc modulates the activity of cytochrome p450 enzymes, particularly CYP2E1, which is involved in phase I detoxification. In phase II, it enhances the activity of glutathione-related enzymes and increases hepatic glutathione levels.⁶² Zinc supports phase III by upregulating metallothionein (MT) and Nrf2 pathways. MT is crucial for binding and sequestering heavy metals while Nrf2 regulates the expression of antioxidant proteins that protect against oxidative damage.⁶³   

Zinc is also beneficial for stabilizing cellular membranes and DNA and protects hepatocytes from apoptosis and genotoxicity induced by toxicants like aflatoxin B1.⁶⁴ 

Selenium 

Selenium is a crucial component of selenoproteins, such as glutathione peroxidase (GPx), which play a significant role in neutralizing ROS and supplementing selenium has been shown to increase GPx activity^{.65 66} Selenium may also induce phase II enzymes like GSTs and modulate the Nrf2 pathway for phase III.^{67 68} 

Another property of selenium is its ability to mitigate liver damage induce by heavy metals like cadmium and mercury.⁶⁹  

Magnesium 

Adequate magnesium helps ensure that cytochrome p450 enzymes function optimally by maintaining cellular energy metabolism and mitochondrial function.⁷⁰ In phase II, magnesium enhances the activity of enzymes such as glutathione-S-transferases (GSTs). Furthermore, magnesium supplementation has been shown to modulate inflammatory signaling pathways and prevent hepatocyte damage.⁷¹  

Key Liver Support Nutrients

Glutathione 

Glutathione (GSH) is a critical intracellular antioxidant that directly scavenges ROS and reactive nitrogen species (RNS), therefore protecting hepatocytes from oxidative stress.⁷²  In phase II, GSH plays a pivotal role by conjugating with xenobiotics and endogenous metabolites through the action of GSTs.⁷³ Lastly, GSH modulates the Nrf2 pathway and enhances upregulation of genes involved in GSH synthesis and utilization.⁷⁴  

N-acetyl cysteine (NAC) 

N-acetyl cysteine (NAC) is a precursor to GSH, a critical antioxidant that helps neutralize reactive intermediates and facilitate their excretion.⁷⁵ Beyond supporting GSH levels and functions, NAC also directly scavenges ROS and enhances the antioxidant enzymes such as GPx and catalase (CAT).⁷⁶  Additionally, sulfur donors like NAC, organosulfur in allium vegetables, and sulforaphane from cruciferous vegetables have been shown to induce phase II enzymes.⁷⁷  

Alpha-lipoic Acid (ALA) 

Alpha-lipoic acid (ALA) serves as both a water- and fat-soluble antioxidant, and evidence suggests that supplementation may support the regeneration of other antioxidants like vitamin C and vitamin E – thereby enhancing the liver’s defense against oxidative damage.⁷⁸ ALA activates Nrf2 which, in turn, up-regulates the expression of various antioxidant and detoxification enzymes and may also mitigate liver damage induced by hepatotoxic agents, including carbon tetrachloride and acetaminophen.^79,80  

Calcium-D-Glucarate (CDG)/D-Glucaric Acid 

D-glucaric acid, along with its salts (including calcium-d-glucarate), supports liver detoxification by reducing ROS production, inhibiting β-glucuronidase, and may have evidence of downregulating hepatocyte apoptosis.⁸¹  

Bioflavonoids and Polyphenols  

Sulforaphane 

Sulforaphane, found in cruciferous vegetables like broccoli, is a potent inducer of GSTs in phase II detoxification and a Nrf2 activator.⁸² Some evidence suggests sulforaphane has been shown to induce the expression of multidrug resistance associated proteins (MRPs), the key efflux transporters in the liver.⁸³  

Silymarin 

Milk thistle (Silybum marianum) is widely recognized for its active component, silymarin, which has antioxidant properties and may support healthy inflammatory function.⁸⁴ Compounds such as silymarin, curcumin, EGCG, and quercetin have been shown to modulate the activity of cytochrome P450 enzymes and provide antioxidant protection in phase I detoxification.⁸⁵ Silymarin supplementation may also protect the liver from damage caused by agents such as acetaminophen and carbon tetrachloride.⁸⁶  

Curcumin 

Curcumin, a polyphenol derived from turmeric (Curcuma longa), modulates cytochrome p450 enzymes, particularly CYP1A1, CYP1A2, and CPY3A4, and increases the activity of GSTs and quinone reductase (QR).^87,88 Curcumin has additionally been documented to activate Nrf2 and upregulate antioxidant response elements, thereby supporting the expression of phase III transporters.⁸⁹  

EGCG 

Epigallocatechin-3-gallate (EGCG) is a polyphenol derived from green tea. Like curcumin, EGCG also modulates the same CYP enzymes in phase I.⁹⁰ EGCG is a potent inducer of phase II enzymes: GST, GPx, and NAD(P)H quinone oxidoreductase 1 (NQO1).⁹¹ It has been shown to activate the Nrf2 pathway, enhancing the expression of detoxification enzymes and efflux transporters.⁹²  

Dandelion Root  

Dandelion root (Taraxacum officinale) has been shown to increase hepatic antioxidant activities, including catalase, GST, GPx, and GSH reductase.⁹³ It also exerts hepatoprotective effects by having the ability to reduce fibrinous deposits and to support a healthy hepatic inflammatory response.⁹⁴  

Artichoke Extract  

Artichoke extract (Cynara scolymus) not only upregulates enzymatic reactions in phase I and phase II detoxification, but it also exhibits choleretic activity and has been shown to increase bile flow and the formation of bile compounds.^95,96 This is crucial for the excretion of conjugated toxic substances. 

Quercetin 

Quercetin is a flavonoid present in many fruits, vegetables, and grains. Quercetin modulates CYP450 enzymes in phase I and is a potent inducer of phase II enzymes (GST and NAD(P)H quinone oxidoreductase-1 (NQO1)) and the Nrf2 pathway in phase III.^97,98 

Resveratrol 

Resveratrol is a natural polyphenol found in fruits that has similar actions to the other bioflavonoids previously mentioned. However, resveratrol uniquely also induces the expression of UDP-glucuronosyltransferase (UGT) enzymes, which are crucial for glucuronidation in phase II.^99,100  

Amino Acids 

Although amino acids such as glycine, taurine, methionine, and glutamine may not have overarching effects on detoxification and hepatoprotection as compared to the other nutrients we’ve covered thus far, their function in supporting liver health is of note.  

Glycine is involved in the synthesis of glutathione.¹⁰¹ Taurine, synthesized from methionine and cysteine in the liver, has significant antioxidant properties and plays a role in phase II amino acid conjugation.¹⁰²  Methionine is a precursor of SAMe and plays a role in transmethylation and transsulfuration pathways in phase II.¹⁰³ Lastly, glutamine enhances bile acid secretion, plays a role in phase II conjugation, and may also activate the Nrf2 pathway.^104,105  

Binders for General Detoxification 

The final category of supplements and nutrients to keep in mind when enhancing liver detoxification are “binders”. Binders, or binding agents, also aid in removing toxic substances from the body. These substances work by adsorbing toxic substances and metabolic byproducts, preventing their reabsorption into the bloodstream, facilitating their excretion through the digestive tract. This in turn lowers the burden on the liver and kidneys, while also potentially supporting the integrity of the gut barrier.^106,107,108 Some of the binders clinicians commonly use include activated charcoal, zeolite or bentonite clay, humic and fulvic acids, chlorella and soluble fiber products like psyllium husk, glucomannan, apple pectin, and modified citrus pectin (MCP).  

Summary 

References 

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