The human body has an amazingly efficient detoxification system, mostly located in the liver. In healthy people, these detoxification processes are in balance, and most of the time function well. However, some diseases, vitamin deficiency, exposure to tobacco smoke, alcohol, and some drugs can upset the balance between detoxification enzymes. Find out which nutrients can help you restore that balance, and how you can help your body detoxify.
1) Overview of the Detoxification Metabolism
Modern life is based on the use of chemicals. The current count of individual substances is now approaching 100 million, and humans and other species are exposed to a great number of them .
Our bodies process and remove these foreign chemicals (xenobiotics) thanks to our efficient detoxification mechanisms. These mechanisms also deal with metabolic products such as excess hormones (endobiotics).
The xenobiotic metabolism usually converts fat-soluble compounds into more water-soluble derivatives that can be easily eliminated from the body .
“Enzymes of detoxification” represent a family of enzymes that participates in altering xenobiotics (i.e. foreign compounds), so as to make them either more readily excretable or less pharmacologically active .
The detoxification process can be roughly divided into three phases :
- Phase I is governed by transformation enzymes – these enzymes oxidize, reduce and hydrolyze toxins/drugs
- Phase II is managed by conjugation enzymes – these enzymes conjugate Phase I products
- Phase III is carried out by transport proteins – these proteins transport the final products from the cell
Phases I, II, and III must work in unison for proper removal of unwanted toxins or drugs or endobiotics such as excess hormones.
These enzymes have broad substrate ranges. They are relatively more concentrated at major points of entry to either the body (liver, lung, intestinal mucosa) or a specific organ (the choroid plexus for the brain). Many also appear to be inducible, i.e. the body responds to exposure to a certain toxin by producing more of the enzyme that degrades it .
The liver is the primary detoxification organ, as it filters blood coming directly from the intestines and prepares toxins for excretion from the body . Significant amounts of detoxification also occur in the intestine, kidney, lungs, and brain, with phase I, II, and III reactions occurring throughout the rest of the body to a lesser degree.
The enzymes of detoxification are slow compared to other enzymes, but they are present in very large amounts. For example, the Phase II glutathione transferases represent 10% of the total protein in the liver .
2) The Three Phases of Detoxification
2.1) Phase I Detoxification – Enzymatic Transformation
Phase I enzymes begin the detoxification process by chemically transforming fat-soluble compounds into water-soluble compounds. Water soluble compounds can easily be excreted, while fat-soluble compounds can be stored in fat cells, where they are protected from the body’s detoxification enzymes.
Phase I reactions include oxidation, reduction, hydrolysis and cyclization .
These reactions are mediated by the versatile cytochrome P450 (CYP) enzymes and the more selective flavin-containing monooxygenases (FMOs, responsible for the detoxification of nicotine from cigarette smoke), monoamine oxidases (MAOs, which break down serotonin, dopamine, and epinephrine in neurons), alcohol and aldehyde dehydrogenases (which metabolize alcohol), epoxide hydrolases (EH) and other phase I enzymes [1, 5, 6, 7, 8].
2.1.1) Cytochrome P450 monooxygenases
Through their unique oxidative chemistry, cytochrome P450 monooxygenases (CYPs) catalyze the elimination of most drugs and toxins from the human body . The CYPs metabolize polycyclic aromatic hydrocarbons, aromatic amines, heterocyclic amines, pesticides, and herbicides, and the vast majority of other drugs .
The Human Genome Project identified 57 human CYPs . However, about 12 hepatic CYPs are responsible for the metabolism of the majority of drugs and other xenobiotics (approximately 93% of the drug metabolism) [1, 4].
Note that although CYPs are detoxification enzymes, these reactions often convert less toxic molecules into more toxic active products. That is where the phase II detoxification steps in.
We differ in our CYPs
More than 2,000 mutations in CYP genes have been described, and certain single nucleotide polymorphisms (SNPs) have been shown to have a large impact on CYP activity .
Genetic polymorphisms, which were shown to depend on ethnicity, play a major role in the function of CYPs (especially CYP2D6, CYP2C19, CYP2C9, CYP2B6, CYP3A5, and CYP2A6), and lead to distinct pharmacogenetic phenotypes termed as poor, intermediate, extensive, and ultrarapid metabolizers .
Individuals in a population can be stratified according to metabolic ratios of particular CYPs. For example, the most frequent phenotype of CYP2D6 is extensive-metabolizer (78.8%). In other words, 78.8% of us are extensive metabolizers. This group is followed by intermediate- (12.1%), poor (7.6%) and ultra-rapid metabolizers (1.5%) .
A CYP2D6 poor metabolizer should not be administered codeine since the drug would have no effect. Conversely, a CYP2D6 ultra-rapid metabolizer would likely suffer side effects from a normal dosage .
A polymorphism in CYP2C19, CYP2C192, was shown to lead to a 30% increased risk of major adverse cardiovascular events during treatment with clopidogrel. On the other hand, CYP2C1917 can increase the risk of bleeding during clopidogrel therapy .
Factors that Influence CYPs
The figure above shows the proportion of drugs metabolized by CYP enzymes. Important variability factors are indicated by bold type with possible directions of influence indicated by arrows. Factors of controversial significance are shown in parentheses .
Sex: Most clinical studies indicate that women metabolize drugs more quickly than men. This is particularly the case with the major drug metabolizing CYP3A4. Analyses have shown ~2-fold higher levels of CYP3A4 protein in female compared to male liver tissue .
Disease: Disease states generally have a negative effect on drug metabolism capacity. During infection, inflammation, and cancer, circulating proinflammatory cytokines such as IL-1β, TNF-α and IL-6 lead to severe downregulation of many drug metabolizing enzymes .
Patients with chronic kidney disease (CKD) have reduced cytochrome P450 (CYP) enzyme activity .
A diet high in saturated fats activates CYP2E1, the enzyme that was shown to be upregulated in diabetes .
Herbs, Foods, and Compounds that Can Decrease CYP activity:
- Compounds found in grapefruit juice and some other fruit juices, including bergamottin, dihydroxybergamottin, and paradicin-A, have been found to inhibit CYP3A4, leading to increased bioavailability of CYP3A4-mediated drugs. These compounds thus increase the possibility of overdosing .
- Starfruit juice inhibits CYP2A6, CYP1A2, CYP2D6, CYP2E1, CYP2C8, CYP2C9 and CYP3A4 .
- Watercress inhibits CYP2E1, which may result in altered drug metabolism for individuals on certain medications (e.g., chlorzoxazone) .
- Goldenseal, with its two notable alkaloids berberine and hydrastine, has been shown to inhibit CYP2C9, CYP2D6, and CYP3A4 [23, 24].
- Eurycoma longifolia, Labisia pumila, Echinacea purpurea, Andrographis paniculata, and Ginkgo biloba inhibit CYP2C8 .
- Propolis inhibits CYP1A2, CYP2E1, and CYP2C19 .
- Lycopene, a red pigment found in tomatoes, carrots, and watermelon, inhibits CYP1A1 and CYP1B1 .
- Licochalcone A, a major compound in traditional Chinese herbal licorice, significantly inhibits CYP1A2, CYP2C19, CYP2C8, CYP2C9, and CYP3A4 and exhibits weak inhibitory effects on CYP2E1 and CYP2D6 .
- Caffeic acid and quercetin, commonly found in plants, potently inhibit CYP1A2 and CYP2C9. Caffeic acid further inhibits CYP2D6 and weakly inhibits CYP2C19 and CYP3A4. Quercetin potently inhibits CYP2C19 and CYP3A4 and moderate inhibits CYP2D6 .
- Ginger extract inhibits CYP2C19 .
- Kale ingestion, unlike that of other cruciferous vegetables, may inhibit CYP3A4, CYP1A2, CYP2D6, and CYP2C19 .
- Piperine, a constituent of black pepper, decreases CYP3A4 .
- Oleuropein, derived from olive oil, inactivates CYP3A4 and slightly inhibits CYP1A2 .
- Garlic inhibits CYP2E1 .
- Resveratrol and garden cress inhibit CYP3A4 .
- Berries and their constituent ellagic acid may reduce CYP1A1 overactivity .
- Apiaceous vegetables may attenuate excessive CYP1A2 action .
- Chrysoeriol, present in rooibos tea and celery, may inhibit CYP1B1 .
- N-acetyl cysteine, ellagic acid, green tea, black tea, dandelion, chrysin, and medium chain triglycerides (MCTs) may downregulate CYP2E1 .
- Saint-John’s wort decreases CYP1A1, CYP1B1, and CYP2D6 .
Herbs, Foods, and Compounds that Can Increase CYP activity:
- Tobacco smoke induces CYPs .
- Common valerian increased the activity of CYP3A4 and 2D6 .
- Ginkgo biloba increased the activity of CYP1A2 and CYP2D6 .
- 17β-estradiol (E2) at high concentrations reached during pregnancy, increases CYP2B6 expression .
- Broccoli and cruciferous vegetables induce CYP1A1/1A2 .
- Resveratrol and resveratrol-containing foods enhance CYP1A1 .
- Curcumin may upregulate 3A4 activity .
- Rooibos tea, garlic, and fish oil appear to induce the activity of CYP3A, 3A1, and 3A2 .
- Saint-John’s wort can increase CYP3A4 [37, 38].
Note that many foods appear to act as both inducers and inhibitors of CYP enzymes, based on their concentration or composition (curcumin/turmeric, black tea/ theaflavins, soybean) . while other foods increase particular CYP enzymes while decreasing others.
It is also important to know that elevated Phase I activity is not always a good thing. As Phase I enzymes produce toxic and carcinogenic compounds, you want them to be in balance with Phase II enzymes.
Receptors that Activate CYP enzymes
The expression of phase I genes is governed by a number of nuclear receptors, including aryl hydrocarbon receptors (AhR), PPARα and orphan nuclear receptors such as constitutive androstane receptors (CAR) and pregnane X receptors (PXR) [3, 17].
- Polycyclic aromatic hydrocarbons (PAHs) activate Ahr, which in turn increases CYP1A and CYP1B enzymes . This is an example where CYPs 1A and 1B oxidize PAH and aromatic amines to carcinogenic products .
- PXR binds small molecules such as steroids, rifampicin, and metyrapone, and increases CYP3A .
- CAR binds phenobarbital, orphenadrine and other drugs that activate CYP2B .
- Clofibrate and other chemical peroxisome proliferators activate PPARα, thereby inducing CYP4A .
2.2) Phase II Detoxification – Enzymatic Conjugation
Through phase I transformation, the fat-soluble toxin is converted into a more water-soluble form. However, phase I reactions are not always sufficient to make the toxin water-soluble enough and in many cases, they render the products more reactive, which makes the toxins potentially more destructive. This is where the phase II enzymes kick in.
Phase II enzymes increase the solubility and reduce the toxicity of phase I products .
Phase II enzymes play a major role in the cellular detoxification of damaging, genotoxic and carcinogenic chemicals .
Gene polymorphisms and/or a lack of these enzymes play a role in several forms of cancer .
Phase II enzymes contain several superfamilies of conjugating enzymes. Among the most important are UDP-glucuronosyltransferases (UGT), glutathione S-transferases (GST), sulfotransferases (SULT), N-acetyltransferases (NAT), and methyltransferases (MT) .
2.2.1) UDP-glucuronosyltransferases (UGTs)
UGT enzymes are responsible for the metabolism of many xenobiotics (drugs, chemical carcinogens, environmental pollutants, and dietary substances) and endobiotics (bilirubin, steroid hormones, thyroid hormones, bile acids, and fat-soluble vitamins) .
In humans, approximately 40–70% of all clinical drugs are metabolized by UGTs .
The monoamine neurotransmitters, dopamine, and serotonin are also processed by UGTs .
UGTs are found throughout the body, in the intestines, kidney, brain, pancreas, and placenta, but most of them are found in the liver .
In the brain, UGTs actively participate in the overall protection against the intrusion of potentially harmful substances .
There are 18 functional UGT enzymes in humans, belonging to two gene families, UGT1 and UGT2, that are, further divided into three subfamilies: UGT1A, UGT2A, and UGT2B .
UGTs process and inactivates toxins such as:
- Cancer-causing polycyclic aromatic hydrocarbons (PAHs) , including benzopyrene, found in cigarette smoke, wood smoke, and burnt foods .
- Bisphenol-A (BPA), a ubiquitous environmental toxin used in plastics and associated with various human diseases including breast cancer .
- Some nitrosamines found in tobacco smoke .
- Heterocyclic amines (HACs), found in red processed meat. 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), the most mass abundant carcinogenic HA found in well-done cooked meat, is extensively glucuronidated by UGT1A proteins .
- Some fungal toxins found in crops .
- Aromatic amines .
Over 10% of the population have hereditary deficiencies in UGTs . Hence, UGTs could constitute an important determinant of susceptibility to chemical carcinogenesis, teratogenesis, and neurodegeneration .
Enhanced UGT activities might lead to more efficient detoxification of carcinogenic compounds and thus could contribute to the prevention of gastrointestinal and other cancers .
We differ in UGTs
Patients with a very rare inherited disorder, the Crigler-Najjar syndrome have a complete or partial absence of UGT1A1. Complete UGT1A1 absence results in high levels of unconjugated bilirubin, severe jaundice, and often brain damage in infants. Patients with a partial deficiency of this enzyme are less severely jaundiced and generally survive into adulthood without neurological or intellectual impairment .
Gilbert syndrome is an autosomal dominant hereditary disorder caused by a mutation in the UGT1A1 gene causing mild hyperbilirubinemia. Gilbert syndrome is found in approximately 10% of the population  and has been strongly associated with altered xenobiotic glucuronidation .
For example, a UGT1A1*28 gene variant results in 30 – 40% lower UGT1A1 levels. When people with this variant are exposed to well-cooked red meat, they exhibit higher urinary mutagenicity (in other words, less of the mutagenic compounds are inactivated) .
Factors that Influence Glucuronidation (UGTs)
- Analgetics, nonsteroidal anti-inflammatory drugs (NSAID), antiviral drugs, anticonvulsants, and anxiolytics/sedatives can inhibit drug glucuronidation .
- Further, some drugs (analgesics, antivirals, and anticonvulsants) may also act as UGT- inducers .
- Cruciferous vegetables, resveratrol, and citrus induce UGT enzymes. However, the effects vary depending on gender and gene variants .
- Dandelion, rooibos tea, honeybush tea, rosemary, soy, ellagic acid, ferulic acid, curcumin, and astaxanthin potentially enhanced UGT activity in animal studies .
- Lycopene, a red pigment found in tomatoes, carrots, and watermelon, increases UGT activity .
Beta-glucuronidase is an enzyme produced by gut bacteria and intestinal cells. Beta-glucuronidase removes (deconjugates) glucuronic acid from neutralized toxins – reversing the reaction catalyzed by UGTs, and reverting the toxins to their previous form .
A high-fat diet may increase beta-glucuronidase activity .
Elevated beta-glucuronidase activity is associated with an increased risk of various cancers, particularly hormone-dependent cancers such as breast, prostate, and colon cancers .
Polyphenol extracts of certain berries, specifically strawberries and blackcurrant inhibit beta-glucuronidase activity in animal studies .
D-glucaric acid, found in many fruits, vegetables, and legumes, may inhibit this enzyme, but human studies have failed to prove this .
2.2.2) Glutathione S-transferases (GSTs)
Glutathione S-transferases (GSTs) catalyze the transfer of glutathione – an important cellular antioxidant, to xenobiotic compounds .
Apart from processing xenobiotics, GSTs protect against oxidative stress , and function as a defense against reactive oxygen species (superoxide radical and hydrogen peroxide) that arise through normal metabolic processes. Many of these are formed by phase I reactions catalyzed by CYPs and other oxidases .
GSTs are widely distributed throughout the body and can be found in liver, kidney, brain, pancreas, testis, heart, lung, small intestine, skeletal muscle, prostate and spleen .
There are many GSTs, divided into two distinct super-families: the membrane-bound microsomal and cytosolic GSTs. Microsomal GSTs play a key role in the endogenous metabolism of leukotrienes and prostaglandins. Human cytosolic GSTs are highly polymorphic and can be divided into six classes: α, µ, ω, π, and ζ (designated by Greek letters) .
GSTs process and inactivates toxins such as:
- α,β-unsaturated carbonyls, many of which are toxic, mutagenic and carcinogenic .
- Polycyclic aromatic hydrocarbons (PAHs), which are found in cigarette smoke, diesel fuel and grilled meats .
Extended life span in animals was associated with significantly higher levels of GSTs .
We differ in GSTs
Depending on the population, approximately 50% of people lack GSTM1 and the same is true for GSTT1. GSTM1 deletion was seen in 53% of whites, in 40 – 60% of Asians, and 21% of African Americans, while GSTT1 deletion was found in 18% of whites, 22% of African Americans, and 45 – 60% of Asians [57, 62].
The dual GSTM1/GSTT1 deletion was associated with higher serum iron and total and LDL-cholesterol concentrations, and lower malondialdehyde concentrations .
Lack of GSTM1, GSTT1, and GSTP1 genes was associated with a higher incidence of some cancers, but the associations were weak. Loss of these genes has also been found to somewhat increase susceptibility to asthma and allergies, atherosclerosis and rheumatoid arthritis .
Variants in omega-class GSTs are associated with the age of onset of neurological diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis .
Factors that Influence GSTs
- Synthetic and naturally occurring phenols, quinones, dopamine or derivatives of vitamin C inhibit GSTs .
- Extracts of Ginkgo biloba have been found to induce GSTP1 and elevated cellular GST activity .
- Extracts from cruciferous vegetables (e.g. broccoli, Brussels sprouts, cabbage) as well as grapefruit extract, and limonene (found in citruses) induce GSTs [39, 64, 65].
- Allium vegetables, resveratrol, fish oil, black soybean, purple sweet potato, curcumin, green tea, rooibos tea, honeybush tea, ellagic acid, rosemary, ghee, and genistein also induce GSTs [32, 65].
- GSTs are also induced by butyrate, a product of gut flora-derived fermentation of plant foods .
- Insulin administration increases GST, while glucagon decreases GST gene expression .
Nutrients that increase the production of glutathione, essential for GST function include vitamin B6, magnesium, selenium, curcuminoids (from turmeric), silymarin (from milk thistle), folic acid, alpha-lipoic acid, cruciferous vegetables and artichoke .
2.2.3) Sulfotransferases (SULTs)
Sulfotransferases (SULTs) are responsible for sulfonation, a reaction that attaches sulfates to endo- or xenobiotics.
SULTs are important for the biotransformation of numerous xenobiotics such as drugs and chemicals , but they also play a significant role in the metabolism of endogenous compounds, such as steroids, catecholamines, serotonin, iodothyronines, eicosanoids, some tyrosine-containing peptides, retinol, 6-hydroxymelatonin, ascorbate and vitamin D .
On the other hand, a number of compounds (procarcinogens) can be converted by SULTs into highly reactive intermediates which can act as chemical carcinogens and mutagens by damaging DNA .
In humans, three SULT families, SULT1, SULT2, and SULT4, have been identified that contain at least thirteen distinct members .
SULTs process and inactivates toxins such as:
- monocyclic phenols .
- naphtols .
- benzylic alcohols .
- aromatic amines .
- hydroxylamines (possible mutagens) .
SULTs also process and inactivate dopamine and iodothyronines .
Sulfonation of aromatic hydroxylamines by SULT1A2 is an example of a toxification reaction, where the sulfoconjugates of hydroxylamines are chemically reactive and mutagenic, and therefore more toxic than the original compounds .
We differ in SULTs
Factors that Influence SULTs
- Grapefruit juice, orange juice, green tea, black tea, and oolong tea can inhibit SULTs .
- Curcumin is a potent inhibitor of SULT1A1 in human liver .
- Quercetin inhibits SULT1A1 .
- Some non-steroidal anti-inflammatory agents can inhibit SULT1A1 and SULT1E1 .
- Wine anthocyanins and flavonols, apple and grape juice, catechins, quercetin, curcumin, resveratrol, flavonoids (apigenin, chrysin, fisetin, galangin, kaempferol, quercetin, myricetin, naringenin, and naringin), and certain phytoestrogens (daidzein, genistein) may also inhibit SULTs, but these have yet to be proven in human and animal studies .
- Retinoic acid can increase SULTs .
- Genistein, a natural isoflavone found in soybean products, induces SULT1A1 and SULT2A1 .
2.2.4) N-acetyltransferases (NATs)
Arylamine N-acetyltransferases (NATs) are responsible for acetylation – a major route of biotransformation for many arylamine and hydrazine drugs, and for carcinogens present in the diet, cigarette smoke and the environment .
NATs process and inactivates toxins such as:
- aromatic amines, many of them carcinogens .
- hydrazine, a highly toxic foaming agent used for industrial and pharmacological purposes .
- drugs such as isoniazid (antituberculosis drug), hydralazine (antihypertensive drug) and sulphonamides (antibacterial drugs) .
We differ in NATs
Based on the differences in NAT genes, humans can be slow, intermediate or rapid acetylators .
When it comes to NAT1, about 8% of the individuals are slow acetylators, but the percentage can be much higher in some regions of the world, such as Lebanon .
In Caucasian and African populations, the frequency of the slow NAT2 acetylation phenotype varies between 40 and 70%, while that of Asian populations, such as Japanese, Chinese, Korean, and Thai, ranging from 10 to 30% .
Rapid NAT2 acetylator phenotype has been linked to the increased risk associated with Alzheimer’s disease. By contrast, the slow phenotype appears to increase the risk of Parkinson’s disease .
The rapid acetylator phenotype has emerged as a strong risk factor for colorectal cancer in those individuals who have a higher exposure to food-derived heterocyclic amines . But there is also an association between NAT2 slow acetylation genotype and the risk of developing several other forms of cancer .
Factors that Influence NATs
- Caffeic acid, esculetin, quercetin, kaempferol, and genistein inhibit NAT1 .
- Scopoletin and coumarin inhibit NAT2 .
- Diallyl sulfide (DAS) and diallyl disulfide (DADS), major components of garlic, inhibit NAT activity .
- Androgens induce NAT1 .
2.2.5) Methyltransferases TPMT and COMT
Thiopurine S-methyltransferase (TPMT) catalyzes the methylation of aromatic heterocyclic sulfhydryl compounds including anticancer and immunosuppressive thiopurines (drugs used to treat acute lymphoblastic leukemia, autoimmune disorders, inflammatory bowel disease, and organ transplant recipients) .
Impaired activity of TPMT causes an accumulation of thiopurine nucleotides, which can lead to cytotoxicity and to the failure of blood cell production (hematopoiesis) .
TPMT levels are highest in the liver and kidney and relatively lower in brain and lungs .
No endogenous substrate is known for this enzyme and its biological role remains unidentified.
TPMT genetic variants
Approximately 1 in 300 Caucasians is homozygous for a defective allele or alleles for the trait of very low activity, ∼11% of people are heterozygous and have intermediate TPMT activity .
Humans with genetically determined low or intermediate TPMT activity have a higher risk for side-effects when treated with standard doses of thiopurines. On the other hand, individuals with high TPMT activity have a lower risk of toxicity but the optimal concentration of drugs in the blood cannot be achieved. In this instance, there is an increased risk of leukemia relapse .
Catechol-O-methyltransferase (COMT) is responsible for methylation of the catecholamine transmitters (norepinephrine, epinephrine, and dopamine). COMT plays a key role in the modulation of catechol-dependent functions such as cognition, cardiovascular function and pain processing. COMT also processes drugs with catechol structure used in the treatment of hypertension, asthma and Parkinson’s disease .
COMT genetic variants
The level of COMT enzyme activity (low, intermediate and high levels) is genetically polymorphic. A common functional genetic polymorphism in the COMT gene may contribute to the etiology of alcoholism .
Factors that Influence TPMT and COMT
- TPMT activity is higher in men than women .
- Naproxen, mefenamic and tolfenamic acid, Olsalazine, 5-aminosalicylic acid and sulphasalazine inhibit TPMT .
- Ketoprofen and ibuprofen are weak inhibitors of TPMT .
- Flavonoid quercetin found in green tea inhibits COMT .
- High sucrose diet may inhibit COMT .
2.2.6) Amino acid conjugating enzymes
Amino acid conjugation is a detoxification pathway for a limited number of xenobiotic carboxylic acids. It involves two groups of enzymes, Acyl-CoA synthetases, and Acyl-CoA amino acid N-acyltransferases .
Not much is known about their detoxification roles yet .
2.3) Phase III Detoxification – Transport
2.3.1) ABC Transporters
Phase III of detoxification is responsible for eliminating toxins and metabolic products from cells.
Phase III transporters can be found in the liver, intestine, kidney, and brain, where they act as a barrier against drug entry, and manage endobiotic and xenobiotic absorption, distribution, and excretion .
These transporters are called ABC transporters (ATP-binding cassette transporters) , and they require ATP to transport a broad range of compounds across the cell membrane . Some of these transporters are also called multidrug resistance proteins (MRPs), because of their involvement in multidrug resistance .
2.3.2) Bile Secretion
Note that, although not officially a part of the 3 -phase detoxification process, bile secretion is necessary for the elimination of toxic endo- and xenobiotics such as bilirubin, lipid bacteria products (endotoxin), and several inflammatory mediators. These products are removed through the intestines .
Impairment of bile flow can result in the buildup of liver toxins and liver injury.
Dietary Factors that can Improve Bile Flow
3) Phase II/Phase I Activity Ratio is Important
Phase I detoxification can produce toxic metabolites. This is not a problem when the phase II enzymes are working well because they efficiently neutralize toxic phase I products as they form.
However, in some cases, this balance between phase I and phase II activity can become uncoupled, leading to the production of toxic metabolites that cannot be timely detoxified, causing cellular and DNA damage .
3.1) Factors that increase phase I over phase II metabolism include:
- smoking – PAHs from cigarette smoke .
- aryl amines from charbroiled meats .
- alcohol consumption .
- glucocorticoids and anticonvulsants .
3.2) Increase Phase II activity by activating Nrf2
Nrf2 activators can control or prevent a wide array of human diseases associated with oxidative stress .
A number of plant-derived compounds with antioxidant activities accomplish their beneficial effects through Nrf2, and the subsequent Phase II detoxification:
- Isothiocyanates, such as sulforaphane found in broccoli [82, 83], and 6-methylsulfinylhexyl isothiocyanate (6-HITC) found in Japanese horseradish [84, 85].
- Resveratrol, found in peanuts, grapes, and red wines .
- Ellagic acid found in blackberries, cranberries, pecans, pomegranates, raspberries, strawberries, walnuts, wolfberries, and grapes [80, 86].
- Curcumin found in turmeric .
- CAPE, caffeic acid phenethyl ester; from honeybee hives .
- Epigallocatechin gallate, from green tea [82, 87].
- Allyl sulfides found in garlic .
- Xanthohumol, a compound found in hops [82, 88].
- Cinnamaldehyde found in cinnamon .
- Hydroxytyrosol from olives .
- Capsaicin, found in chili peppers.
- Apple polyphenols .
The enhancement of Phase II activity can explain, at least in part, the health-boosting effect of fruits and vegetables, and their cancer-preventing properties .
These supplements can also increase Nrf2 activity:
- Alpha-tocopherol (vitamin E) 
- Chlorophyllin 
- Alpha-lipoic acid 
- Dithiolethiones such as Oltipraz, an organosulfur cancer-preventive compound , and flavonoids such as Chalcone .
4) Heavy Metal Detoxification
There are 23 heavy metals of concern for human health because of residential or occupational exposure: antimony, arsenic, bismuth, cadmium, cerium, chromium, cobalt, copper, gallium, gold, iron, lead, manganese, mercury, nickel, platinum, silver, tellurium, thallium, tin, uranium, vanadium, and zinc .
Heavy metal toxicity can lower energy levels and damage the functioning of the brain, lungs, kidney, and liver .
Heavy metals can cause an increase in the production of reactive oxygen species (ROS). Enhanced generation of ROS can overwhelm cells’ intrinsic antioxidant defenses, and result in oxidative stress. Cells under oxidative stress display various dysfunctions due to lesions caused by ROS to lipids, proteins, and DNA .
Heavy metals can further inactivate glutathione, inhibiting its antioxidant activity .
Long-term exposure can lead to gradually progressing physical, muscular, and neurological degenerative processes that imitate diseases such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and muscular dystrophy.
Chelation is central to natural detoxification of heavy metals. It is achieved when chelators bind metals forming molecular complexes, that can be excreted from the body .
Natural chelators that bind metals in our bodies include metallothioneins, and glutathione .
Metallothioneins (MTs) are cysteine-rich, small metal-binding proteins. MTs both take care of the physiological balance (homeostasis) of essential metals such as zinc and copper and protect against other toxic metals, such as cadmium and lead, by binding them and scavenging free radicals generated in oxidative stress [100, 101, 102].
One molecule of metallothionein can bind 7 atoms of bivalent metals (zinc, cadmium) or a greater number (12 atoms) of univalent ones (e.g. silver) .
Factors that Influence Metallothioneins:
- Conditions like irritable bowel disease (IBD) decreases metallothioneins .
- Zinc supplementation can restore metallothionein concentrations .
- Chromium may inhibit zinc-induced metallothionein expression .
- Hops, pomegranate, prune skin, and watercress can increase metallothioneins. So can sulforaphane from cruciferous vegetables, quercetin and Cordyceps sinensis, a mushroom native to the Himalayan region .
4.2) Foods and Supplements that can Enhance Heavy Metal Detoxification
Some foods have been suggested to reduce absorption or reabsorption of toxic metals and to support natural detoxification pathways:
- Dietary insoluble fibers, including bran from grains as well as fruit, reduced levels of mercury in the brain and blood. However, soluble fiber, such as flaxseed, resulted in increased intestinal absorption of cadmium .
- The algal polysaccharides alginate and chlorella can reduce lead and mercury .
- Diets rich in sulfur-containing foods such as alliums and brassicas can increase glutathione and heavy metal detoxification. For example, garlic prevents cadmium-induced kidney damage and decreases the oxidative damage due to lead in rats .
- Cilantro (leaves of Coriandrum sativum), a popular culinary and medicinal herb, enhanced mercury excretion following dental amalgam removal. In animals, it decreases lead absorption into bone .
Several supplements can also help with metal toxicities:
- Taurine and methionine, sulfur-containing amino acids, decrease oxidative stress markers resulting from heavy metal exposure .
- Alpha lipoic acid has metal-chelating activity. However, clinical experience is that it must be used carefully as it poses a risk of redistribution of metals .
- N-acetyl-cysteine (NAC), an orally available precursor of cysteine, is a chelator of toxic elements and can stimulate glutathione synthesis, particularly in the presence of vitamins C and E .
- Selenium forms an extremely stable, insoluble compound with mercury, and provides relief of mercurialism symptoms. Organic selenium supplementation was beneficial in a controlled trial among 103 mercury-exposed villagers where a selenium yeast product increased mercury excretion and decreased oxidative stress [99, 104].
- Magnesium and zinc supplementation blunt the absorption of cadmium .
- Calcium supplementation reduced lead mobilization from maternal bones during pregnancy and lactation, protecting the newborn and infant . In animals, calcium deprivation enhances the absorption of lead and cadmium .
- In children, iron supplementation blunted lead accumulation .
5) Vitamins and Minerals are essential for Detoxification
For the detoxification reactions to run smoothly, it is important for the body to be vitamin sufficient, because many vitamins and minerals are required either for the reactions themselves or for the production of detoxification enzymes. Vitamins also help with the removal of the toxic products of phase I detoxification .
6) Nutrients and Foods that Help Detoxification – Summary
These are great nutrients to stimulate detoxification enzymes:
- Allium vegetables (garlic, onions, leeks, chives, scallions, and shallots)
- Apiaceous vegetables (carrots, parsnips, celery, parsley)
- Berries (raspberries, blueberries)
- Black tea
- Black pepper
- Broccoli and other cruciferous vegetables (arugula, bok choy, Brussel sprouts, cabbage, kale)
- Caffeic acid (found in plants, with especially high levels in thyme, sage, spearmint Ceylon cinnamon, star anise, and yerba mate)
- Chili peppers
- Ellagic acid (found in blackberries, cranberries, pecans, pomegranates, raspberries, strawberries, walnuts, wolfberries, and grapes)
- Fish oil
- Garden cress
- Green tea
- Honeybush tea
- Olives and olive oil
- Purple sweet potato
- Quercetin (found in many plants, high in red kidney beans and capers)
- Resveratrol (found in peanuts, grapes, and red wines)
- Rooibos tea
- Soybean/Black soybean
7) What Else Helps the Body Detoxify?
Probiotics have many health benefits. One of them is to bind toxins and reduce their toxicity.
Additionally, probiotics produce butyrate, that induces phase II GST enzymes .
7.2) Calorie restriction and intermittent fasting
In turn, high levels of toxins in the adipose tissues can decrease the turnover of fats in order to protect other organs from toxins . This means that toxins accumulated in fat tissue can make it more difficult to lose weight.
The content of persistent organic pollutants (POPs) in adipose (fat) tissues has been reported to be 2-3 times higher in obese compared to lean persons .
Reduced calorie intake without malnutrition, can induce Nrf2, and exhibit anticarcinogenic effects .
However, when fasting, make sure to consume enough fruits and veggies to support those detoxification processes.
Whether it’s a Roman bath, Aboriginal sweat lodge, Scandinavian sauna, Turkish bath or rigorous exercise, sweating can be beneficial.
Sweating can help expel toxic metals from the body, including mercury, arsenic, cadmium, and lead .