Liver detoxification - No dirty stories here
How do we tackle detoxification? There are many things in our modern-day living that contribute to an increased antigenic and toxic burden. These include toxic exposure, leaky gut, yeast, bacteria, parasites, nutrient deficiencies and food allergies.
The liver is responsible to get rid of these toxins in a safe way. Let’s take a look at how this happens and how we can help the detoxification process.
Liver detoxification problems do not paint a pretty picture.
The symptom picture of general toxicity includes increasing sensitivity to exogenous exposures, general malaise, pain, fatigue and headache. Joint and muscle pain and poor exercise tolerance are also symptoms, along with skin rashes, cognitive dysfunction, unilateral paraesthesia and paradoxical responses to medications.
The body easily absorbs non-polar, fat-soluble toxins, yet does note easily excrete them. It has developed enzyme systems to transform these toxins into more polar molecules, making them easier to eliminate through detoxification. This biotransformation may occur in the liver, intestines, lungs, kidneys and the skin.
There are two major pathways of liver detoxification. There is Phase I, which consists primarily of hydroxylation reactions involving cytochrome P450 enzymes – these are highly inducible with wide genetic variability.
Phase II is the second phase of the detoxification process. This phase consists of conjugation reactions.
Phase I Detoxification
In this phase, the liver transforms fat-soluble water-soluble compounds into water-soluble turmeric chilli compounds so the body can excrete them. P450 enzymes can neutralize compounds directly, or convert them into intermediate forms. Toxic intermediates are highly reactive (water-soluble).
Phase I detoxification reactions involve hydroxylation, oxidation, dehydrogenation and epoxide hydration along with metabolic reductions, alcohol dehydrogenation and metabolic de-alkylation.
There are various substances that activate Phase I. Drugs such as alcohol, nicotine, phenobarbital, sulphonamides and steroids.
Certain foods, mainly cruciferous vegetables, char-broiled meats, high protein diet and tangerines as well as nutrients, specifically vitamins B1, B3 and C, and herbs such as caraway and dill also play a role in detoxification.
This list includes environmental toxins such as carbon tetrachloride, exhaust fumes, paint fumes, dioxins and pesticides.
Inhibitors of Phase I detoxification include food such as naringenin (grapefruit juice), curcumin (turmeric), capsaicin (chilli pepper), eugenol (clove oil) and quercetin (onions). Certain medicines may also inhibit Phase I detoxification, specifically benzodiazepines, antihistamines, cimetidine and other stomach-acid secretion blocking medications, ketoconazole and sulfaphenazole. Calendula officianalis, a botanical, may also be a factor, along with ageing and bacterial toxins from the gastrointestinal tract.
Phase II Conjugation Reactions
The reactions of this phase of detoxification consist of glutathione conjugation, amino acid conjugation (glycine, glutamine and taurine), sulfation, glucuronidation, acetylation and methylation.
The test procedure to assess a detoxification profile entails taking 200mg caffeine on waking. The test starts with the collection of a saliva sample collected both two and eight hours later. To complete the process, you would take 650mg aspirin and 650mg acetaminophen at bedtime. 10 hours later, one collects a final urine sample.
A fast Phase I and a deficient Phase II detoxification lead to a generation of toxic intermediates which can damage cells and exert systemic effects. The treatment goals are to reduce toxin exposure, increase antioxidant support and enhance Phase II conjugation, for example by supplementing with N-acetylcysteine (NAC), GSH, glycine, Ca-d glucarate and cofactors etc.
A slow Phase I may be due to impaired detoxification ability. P450 inhibitors need to be ruled out, namely H2 blockers, birth control pills, SSRIs, heavy metal toxicity, naringenin, “Azole” antifungals, certain antibiotics, excess sugar, trans saturated fats and possible iron deficiency. The treatment normally involves the elimination of inhibiting substances with nutritional and hepatic support.
Nutrition for Phase II pathways should include things such as indole-3-carbinol, cruciferous vegetables, garlic, rosemary and soy.
Cysteine to Sulfate Conversion
A normal to high cysteine level with low sulfate may mean low molybdenum or hypochlorhydria which can affect the detoxification process:
- Cysteine dioxygenase to cysteine to sulphite.
- Sulfite to sulfate (requires sulfite oxidase and a molybdenum dependent pathway).
Sensitivity to sulfites is another possibility. Vitamin B6 may need to be supplemented as this vitamin is something you require to convert cysteine to taurine and alpha-ketoglutarate.
Three amino acids make up glutathione; cysteine, glycine and glutamic acid. This highly concentrated intracellular antioxidant acts as a powerful detoxification ally.
Glutathione is a sulfhydryl antioxidant, anti-toxin and enzyme cofactor. It neutralizes free radicals produced in Phase I reactions in the liver. The cell cytosol contains most glutathione as it is water-soluble.
Causes of depleted GSH reserves include excess exposure to xenobiotics or gut-derived toxins. Also, excess production of free radicals due to up-regulated CYP-450 activity, inflammation, trauma, infection, intestinal dysbiosis, radiation and ischemia may affect reserves. Insufficient nutrient cofactors and inadequate GSH precursors/impaired methionine metabolism may also be more causes.
Glutathione cofactors consisting of magnesium (recycles pyroglutamic acid back to GSH), vitamin B6, B12, B2 and folate assist in homocysteine metabolism. Vitamin C can also preserve intracellular cellular GSH concentrations while serine (formed from glycine) is another cofactor.
Glutathione precursors involve reduced GSH and supplementing with NAC, L-methionine, glycine or L-glutamine. Studies suggest using NAC as the least flawed and the most cost-effective oral precursor(Alt Med Rev 1997; 2(3):155-176).
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Glycine is the main component of GSH. An inhibitory neurotransmitter that is involved in the synthesis of DNA, phospholipids and collagen. Salicylates and benzoate are detoxified primarily through glycination.
Depleted glycine reserves may be due to an insufficiency of available glycine and insufficient nutrient cofactors (cysteine, pantothenic acid and magnesium). Both of which boost co-enzyme A which is required for activation of the metabolite to be conjugated.
Underlying hepatic disease and genetic uniqueness may also deplete reserves.
Sulfation involves the conjugation of toxins with sulfur-containing compounds. Toxins such as steroid hormones, thyroid hormones, certain drugs and xenobiotic compounds use sulfation as their primary route of detoxification. Bacterial toxins and environmental toxins also use the sulfation pathway.
Sulfation is the primary route for the elimination of neurotransmitters.
Inadequate sulphate results in an accumulation of toxic metabolites which in turn causes degeneration of the nervous tissue. Poor sulfoxidation may, therefore, increase the susceptibility to Parkinson’s disease and motor neuron diseases.
The causes of depleted sulfation reserves include exposure to xenobiotics and free radicals, insufficient sulphate and nutrient cofactors (methionine, cysteine), and impaired sulfoxidation (cysteine/sulfate ratio). Underlying hepatic disease, an excess of molybdenum and vitamin B6 (100 mg/day) and genetic uniqueness may also influence reserves.
Many commonly prescribed drugs are metabolised through the glucuronidation pathway for example estrogens, melatonin, vitamins A, D, E and K. Glucuronidation is an important detoxification mechanism for when sulfation or glycination is reduced or saturated.
People with Gilbert’s syndrome (reduced bilirubin glucuronosyltransferase) are known to have decreased glucuronidation.
Beta-glucuronidase is an inducible enzyme elaborated by anaerobic E. coli, Bacteroides, clostridia and peptostreptococcus. Elevated levels are associated with increased enterohepatic recirculation of toxins, hormones, drugs and carcinogens. Broad-spectrum antibiotics reduce beta-glucuronidase activity and intestinal reabsorption of estrogen (oral contraceptive pill).
Insufficient CHO reserves (fasting or insulin insensitivity) cause depleted glucuronidation. Free radical mitochondrial damage is another cause, as ATP is required for glucuronidation. Cofactor insufficiency, specifically L-glutamine, aspartic acid, vitamin B3, B6, iron and magnesium, as well as hypothyroidism are causes, and also the antibiotics chloramphenicol and novobiocin.
Detoxification is one of the body’s primary defence mechanisms.
Challenges such as leaky gut, poor diet, toxic chemicals and environmental pollutants increase the toxic burden. Impaired detoxification leads to free radicals and affects many systems in the body. Utilizing the detoxification profile targets specific imbalances and allows for tailored intervention.
Suggested Nutritional Protocol for Detoxification
COMT: Quatrefolic, TMG, SAMe, B vitamins
GSTM and/or GSTT: NAC, Emothion, IV glutathione drips
CYP 1A1 and CYP 1B1 abnormalities: I never do enhancing of phase I without II as well, therefore: I3C & DIM
CYP 17A1 same supplements as for CYP 1A1 and CYP 1B1
ER-alpha: Add estriol (E3) and progesterone to HRT and I3C & DIM
Sult: Multi-being Multimineral
SOD2: glisodin with superoxide dismutase
MTHFR: I use TMG, SAMe and other methyl donors such as Quatrefolic
Vitamin D3: Vitamin D levels above 60