Detoxification – One of the Body’s Primary Defense Mechanisms!

Toxic exposure, leaky gut, yeast, bacteria, parasites, nutrient deficiencies and food allergies all contribute to an increased antigenic and toxic burden.

The symptom picture of general toxicity includes increasing sensitivity to exogenous exposures, general malaise, pain, fatigue and headache. Joint and muscle pain and a poor exercise tolerance are also symptoms along with skin rashes, cognitive dysfunction, unilateral paraesthesia and paradoxical responses to medications.

Non-polar, fat soluble toxins are easily absorbed, but are not easily excreted. The body has developed enzyme systems to transform these toxins into more polar molecules, making them easier to eliminate. This bio-transformation may occur in the liver, intestines, lungs, kidneys and the skin.

There are two major pathways of liver detoxification. Phase I consists primarily of hydroxylation reactions involving cytochrome P450 enzymes – these are highly inducible with a wide genetic variability. Phase II consists of conjugation reactions.



Phase 1
Detoxification

Phase 1 detoxification transforms fat soluble compounds into water soluble 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 1 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. Another is foods, mainly cruciferous vegetables, char-broiled meats, high protein diet and tangerines. Nutrients, specifically vitamin B1, B3 and vitamin C and herbs such as caraway and dill seeds also play a role. Environmental toxins like carbon tetrachloride, exhaust fumes, paint fumes, dioxins and pesticides are also included.

Inhibitors of Phase I detoxification includes foods such as naringenin (grapefruit juice), curcumin (tumeric), capsaicin (chili pepper), eugenol (clove oil) and quercetin (onions). Certain drugs may also inhibit Phase 1, specifically benzodiazepines, antihistamines, cimetidine and other stomach-acid secretion blocking drugs, ketoconazole and sulfaphenazole. Calendula officianalis, a botanical, may also be a factor, along with aging and bacterial toxins from the gastrointestinal tract.



Phase 2
Conjugation Reactions

These reactions 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. A saliva sample is then collected two and eight hours later. At bedtime 650mg aspirin and 650mg acetaminophen is taken and a urine sample is collected for the next 10 hours.
 
A fast Phase 1 and a deficient Phase II 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 NAC, GSH, glycine, Ca-d-glucarate and cofactors etc.
 
A slow Phase 1 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, transaturated fats and possible iron deficiency. The treatment normally involves elimination of the inhibiting substances with nutritional and hepatic support. Nutrition for Phase II pathways should include 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: 

  • 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 it is required to convert cysteine to taurine and alpha ketoglutarate.


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Glutathione
Glutathione is composed of three amino acids; cysteine, glycine and glutamic acid and is a highly concentrated intracellular antioxidant. It is a sulfhydryl antioxidant, anti-toxin and enzyme cofactor. It neutralizes free radicals produced in Phase I reactions. As it is water soluble it is mainly found in the cell cytosol.

Causes of depleted GSH reserves include excess exposure to xenobiotics or gut derived toxins. Also, an 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 preserves intracellular GSH concentrations while serine (formed from glycine) is another cofactor.

Glutathione precursors involve reduced GSH and supplementing with N-acetylcysteine (NAC), L-methionine, glycine or L-glutamine. NAC is however considered the best oral precursor as it is the least flawed and the most cost effective (Alt Med Rev 1997; 2(3):155-176).

Glycine
Glycine is the main component of GSH. It is an inhibitory neurotransmitter involved in the synthesis of DNA, phospholipids and collagen. Salicylates and benzoate are detoxified primarily through glycination.

Causes of depleted glycine reserves may be due to insufficient glycine available and insufficient nutrient cofactors (cysteine, pantothenic acid and magnesium). These 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
Sulfation involves the conjugation of toxins with sulfur-containing compounds. 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.

Glucuronidation
Many commonly prescribed drugs are metabolized through the glucuronidation pathway for example estrogens, melatonin, vitamins A, D, E and K. Glucuronidation is an important detoxification mechanism when sulfation or glycination is reduced or saturated. People with Gilbert’s syndrome (reduced bilirubin glucuronosyl transferase) 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 re-circulation 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.

Conclusion
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.

SNP (single nucleotide polymorphism)     :    
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COMT: methyl donors (Homocysteine Lowering Formula, TMG, SAMe, B vitamins)

GSTM and /or GSTT: NAC, transdermal glutathione, IV glutathione drips

CYP 1A1 and CYP 1B1 abnormalities: I never do enhancing of phase I without II as well, therefore: I3C / DIM / sulphoraphane containing products
Beta-glucoronidase inhibition with calcium d-glucorate is of added benefit

CYP 17A1 same supplements as for CYP 1A1 and CYP 1B1

ER alpha: Add estriol (E3) and progesterone to HRT and I3C / DIM

Sult: Muti Mineral

SOD2:  glisodin with superoxide dismutase

MTHFR: I use TMG, SAMe and other methyl donors such as folate or Homocysteine Lowering Formula or Folinic Acid

Vitamin DR: Vitamin D levels target 60


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Dr Craige Golding