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The
Liver of the Matter Note: The information on this website is presented for
educational purposes and This document was provided by Once thought to be the seat of courage, love etc., the liver is central to our bodies’ endless process of removing unwanted chemicals. Leading British nutritionist and Director of the Society for the Promotion of Nutritional Therapy LINDA LAZARIDES takes a closer look. One of our body’s most vital functions is to convert metabolic products and toxins into safe, soluble substances which can be eliminated via the urine or the gall bladder into the intestines. The liver plays an all-important role in this process – known as detoxification or biotransformation. Recent research has shown that many patients with chronic illnesses have a disordered liver biotransformation ability. We simply don’t know all the diseases and health disorders which may be promoted by a toxic overload resulting from such dysfunction, but progress is beginning to be made in looking at specific detoxification pathways and relating underfunctioning of these to the development of disease. PathwaysA number of biochemical ‘pathways’ – sequences of chemical changes – are involved in liver biotransformation. These are normally grouped into oxidation, reduction or hydrolysis reactions (Phase I) and conjugation reactions (Phase II). Phase I reactions are catalysed by a group of liver enzymes scientifically known as cytochrome P450 oxidases (or P450 oxidases or cytochrome p450s). These enzymes introduce oxygen into the chemical structure of toxins or metabolites. Typically, by this process the toxins are converted into intermediate substances – alcohols and aldehydes – then into acids, which are water-soluble, and can be excreted via the urine. Phase I detoxificationThe intermediate substances created during Phase I detoxification, which include reactive oxygen species (free radicals), can be extremely toxic – far more so than the original toxins. Their harmful effects are primarily controlled by antioxidant nutrients/enzymes: a plentiful supply of these substances is essential. Apart from free radicals, intermediate metabolites include chloral hydrate (which is identical to the knock-out drug often known as a ‘Mickey Finn’), epoxides, and endogenous benzodiazepines – substances similar to Valium and other tranquillisers and sleeping pills. This makes it easier to understand how chronic fatigue, for instance, can develop when a toxic overload is present. The more P450 enzymes are induced in the liver, the more of the toxic intermediates will be present in the body. P450 enzymes are induced by caffeine, alcohol, dioxin and other pollutants, exhaust fumes, high protein diets, oranges and tangerines, organophosphorus pesticides, paint fumes, steroid hormones, and a variety of drugs including paracetamol (acetaminophen), diazepam tranquillisers and sleeping pills, the contraceptive pill and cortisone. AldehydesSubstances which can inhibit the action of P450 enzymes include carbon tetrachloride, carbon monoxide, barbiturates, quercetin and naringenin (found in grapefruit). The oxidation reaction can also be blocked by an excess of toxic chemicals, a lack of enzymes, lack of nutrients and/or loss of oxygen. Such blocking results in a build-up of more toxic substances such as formaldehyde and other aldehydes in tissue. This can in turn lead to a spreading phenomenon, with increasing sensitivity to more chemicals such as ketones and alcohols, and eventually even to natural chemicals occurring in foods, pollen and mould. A build-up of aldehydes can in severe cases lead to tissue cross-linking, causing vasculitis with possible seizures and brain damage. Although most aldehydes in the body are thought to occur as intermediate metabolites, external sources include exposure to formaldehyde gas (which is given off by new carpets, curtains and other furnishings) and breakdown products of ethylene glycol and methanol. Two known sources of aldehydes are intestinal overgrowth with Candida albicans, as well as the peroxidation of polyunsaturated fats. The fatigue, foggy thinking and ‘brain fag’ linked with candidiasis may be due to an overloading of the detoxification system with aldehydes, which can even lead to a reverse reaction of aldehyde to alcohol. Extreme intolerance to alcohol consumption may occur in these individuals, as it does in those diagnosed with ME or chronic fatigue syndrome. AminesCytochrome P450 and other oxidizing enzymes also oxidize amines such as phenylethylamine found in chocolate, tyramine found in cheese, and adrenaline, noradrenaline and dopamine. These are oxidized into aldehydes by the enzyme mitochondrial monoamine oxidase (MAO) – if this enzyme is blocked, for instance by MAO inhibitor drugs used to treat depression, tyramine, for instance, cannot be metabolized and hypertension can develop as a chemical sensitivity reaction. Phase II detoxification (conjugation)There are five main conjugation categories, including acetylation, acylation (peptide conjugation with amino acids), sulphur conjugations, methylations and conju-gation with glucuronic acid. Some substances enter Phase II detoxification directly, others come via Phase I pathways. Conjugation involves the combining of a metabolite or toxin with another substance which adds a hydrophilic (or water-reactive) molecule to it, converting lipophilic (or fat-reactive) substances to water-soluble forms for excretion and elimination. Individual xenobiotics and metabolites usually follow a specific path, so whereas caffeine is metabolized by P450 enzymes, aspirin-based medications are conjugated with glycine, and paracetamol with sulphate. AcetylationAcetylation requires pantothenic acid to function. It is the chief degradation pathway for compounds containing aromatic amines such as histamine, serotonin, PABA, P-amino salicylic acid, aniline and procaine amide. It is also a pathway for sulphur amides, aliphatic amines and complex hydrazines. A proportion of the general population – perhaps up to 50 per cent – are slow acetylators. This rises to as high a level as 80 per cent among the chemically sensitive population. Their N-acetyltransferase activity is thought to be reduced, and this prolongs the action of drugs and other toxic chemicals, thus enhancing their toxicity. AcylationAcylation uses acyl CO-A, with the amino acids glycine, glutamine and taurine. Conjugation of bile acids in the liver with glycine or taurine is essential for the efficient removal of these potentially toxic compounds. Disturbed acylation by pollutant overload decreases proper levels of bile in the gastrointestinal tract, resulting in poor assimilation of lipids and fat-soluble vitamins, and disturbed cholesterol metabolism. Toluene, the most popular industrial organic solvent, is converted by the liver into benzoate, which like aspirin must then be detoxified by conjugation with the amino acid glycine (glycination): large doses of glycine and N-glycylglycine are used in treating aspirin overdose. Benzoate itself is present in many food substances and is widely used as a food preservative. Glycine is a commonly available amino acid, but the capacity to synthesize taurine may be limited by low activity of the enzyme cysteine-sulfinic acid decarboxylase. Damage can occur to this enzyme directly by pollutants, or by overload/over-use resulting in depletion. Both taurine- and glycine-dependent reactions require an alkaline pH: 7.8 to 8.0. Environmental medicine specialists may alkalinize over-acidic patients by administering sodium and potassium bicarbonate in order to facilitate these reactions. Glutathione conjugation, using the amino acid glutathione in its reduced form, is used for the transformation of xenobiotics such as aromatic disulphides, naphthalene, anthracene, phenanthacin compounds, aliphatic disulphides – and the regeneration of endogenous thiols from disulphides. There is a cycle of replenishment for glutathione, allowing it to be reformed after conversion to glutathione reductase. Heavy metals can inhibit this cycle, thus preventing replenishment. Sulphur conjugation (sulphation) Neurotransmitters, steroid hormones, certain drugs and many xenobiotic and phenolic compounds such as oestrone (one of the forms of oestrogen), aliphatic alcohols, aryl amines and alicyclic hydroxy-steroids employ sulphation as their primary route of detoxification. Steventon at Birmingham University (UK) has found that many sufferers from Parkinsonism, motor neurone disease and Alzheimer’s disease as well as environmental illness, tend to have a reduced ability to produce sulphate from the amino acid cysteine in their body, and instead accumulate cysteine. Sulphate may be ingested from food, but is also produced by the action of the enzyme cysteine dioxygenase on cysteine. This process is known as sulphoxidation. The body’s ability to conjugate toxins with sulphate is ‘rate limited’ by the amount of sulphate present; if there is inadequate sulphate, toxins and metabolites can accumulate, perhaps building up to levels which cause degeneration of nervous tissue after several decades. Steventon’s findings are a matter for serious concern. How many individuals are given the opportunity to find out whether they are poor sulphoxidizers and to reduce their chances of developing the above mentioned diseases by improving their sulphoxidation ability? MethylationAccording to environmental medicine specialist William Rae, the process most often disturbed in chemically sensitive people involves methylation reactions catalysed by S-adenosyl-L-methionine-dependent enzymes. Methionine is the chief methyl donor to detoxify amines, phenols, thiols, noradrenaline, adrenaline, dopamine, melatonin, L-dopa, histamine, serotonin, pyridine, sulphites and hypochlorites into compounds excreted through the lungs. Methionine is needed to detoxify the hypochlorite reaction. The activity of the methyltransferase enzyme is dependent on magnesium, and, due to the frequency of magnesium deficiency, supplementation with this nutrient will often stabilize chemically sensitive patients. GlucuronidationGlucuronic acid is a metabolite of glucose. It can conjugate with chemical and bacterial toxins such as alcohols, phenols, enols, carboxylic acid, amines, hydroxyamines, carbamides, sulphonamides and thiols, as well as some normal metabolites in a process known as glucuronidation. For most individuals glucuronidation is a supplementary detoxification pathway. It is a secondary, slower process than sulphation or glycination, but is important if those pathways are diminished or saturated. Obese people seem to have an enhanced capacity to detoxify molecules that can use the glucuronidation pathway. However, damage to the capacity for oxidative phosphorylation which takes place in the mitochondria, is likely to diminish the capacity for glucuronide conjugation. OverloadIf the liver’s detoxification pathways are excessively stimulated and overly utilized, they eventually become depleted or begin to respond poorly – being suppressed by toxic chemicals. Once breakdown of the main pathways occurs as a result of pollutant overload, toxins are shunted to lesser pathways, eventually overloading them, and disturbing orderly nutrient metabolism. Chemical sensitivity may then occur, followed by nutrient depletion and finally fixed-name disease. Depleted immunity is also a potential outcome of a toxic overload. Interesting facts• Dr William Rae of the Environmental Health Centre in Dallas says that the most severely ill chemically sensitive patients not only have abnormally low antipollutant enzymes, in addition to toxic suppression and nutrient depletion, but in some instances antibodies are produced against cytochrome P450 and these may inhibit or decrease its effectiveness. • Environmental medicine specialists have found that almost 35 per cent of chemically sensitive patients are deficient in intracellular sulphur. Not only can this hinder the detoxification of some sulphur-containing and other toxic chemicals, it can enhance the harmful effects of exposure to cyanide from foods such as cassava and almonds as well as from tobacco products. The hereditary disease known as Leber’s optic atrophy involves a defect in the ability to detoxify cyanide, and leads to sudden, permanent blindness on first exposure to cyanide in small amounts such as those ingested from smoking cigarettes. • Many multimineral supplements in the UK omit iron and copper due to theories that individuals may already be overloaded with these nutrients. However if no overload is present, an unbalanced supplement may promote depletion of the minerals. The Environmental Health Centre in Dallas finds that intravenous infusions to replenish iron stores brings dramatic improvements for the chemically sensitive patient as part of their detoxification process. Copper is also found to help catalyse the cytochrome systems. (NB: self-supplementation with iron and copper should be cautious, to avoid iron and copper overload conditions). • Although the liver is the primary site for oxidation of xenobiotics, the cytochrome P450 system is found in other tissues that are exposed to environmental compounds like the skin, lungs, gastrointestinal tract, kidneys, placenta, corpus luteum, lymphocytes, monocytes, pulmonary alveolar macrophages, adrenals, testes and brain, in both the mitochondria and in the nuclear membrane. • Always rinse your washing-up carefully. Pollutants in the form of solvents and detergents can damage and penetrate cell membranes and damage the contents of the cell. • Vitamin B3 has been shown to accelerate the clearance of aldehydes in some chemically sensitive patients. • Molybdenum, although an essential element, competes with sulphate in its activation step to the important enzyme PAPS and can thus lower sulphate levels and impair sulphation ability. Environmental medicine experts warn that molybdenum supplementation may be contraindicated in individuals with poor sulphation ability. • The substance naringenin, found in grapefruit, can significantly inhibit Phase I detoxification, as can grape-fruit itself. This may prove clinically useful in some situations where Phase I activity is too high, (as shown in liver function tests available from nutritional therapists). • Persons who have been exposed to toxic chemicals, drugs and other xenobiotics, have increased requirements for some vitamins. Functional nutritional assays for vitamins B1, B2, B3, B6, B12 and folate, and serum levels of vitamins A, D, C and beta carotene were performed in a random sample of 333 environmentally-sensitive patients prior to treatment. 57.8% were found to be deficient in B6, 37.7% in vitamin D, 34.9% in B2, 32.2% in folate, 27.7% in vitamin C, 21.4% in niacin, 14.9% in B12, 5.6% in vitamin A and 4.6% in beta-carotene. (Ross GH et al: Evidence for vitamin deficiencies in environmentally-sensitive patients. Clinical Ecology 6(2):60-6, 1989.) Adapted from the Nutritional Health Bibleby Linda Lazarides (Thorsons, £9.99). Published September 1997. Available from all good bookshops or by mail order from SPNT Books (see address below). Foods to aid detoxificationBeetroot helps with liver drainage Broccoli, cauliflower and other cruciferous vegetables these aid cytochrome P450 activity Protein Radish, watercress rich in sulphur. Supplements to aid liver detoxificationB complex vitamins Digestive enzymes may be necessary to ensure that protein is adequately digested and glycine is readily available Essential fatty acids N-acetyl cysteine (NAC) Reduced glutathione Selenium, zinc, magnesium and manganese possibly iron and copper if used with caution Taurine (a useful combination product is magnesium taurate) Vitamins C and E and beta carotene. Liver herbs to aid detoxification(traditionally known as ‘blood cleansing’ herbs) Dandelion root cholagogue (stimulates liver secretions and bile flow) Globe artichoke leaf promotes regeneration of the liver and promotes blood flow in that organ Silymarin according to recent research, this herbal extract stabilizes the membranes of liver cells, preventing the entry of virus toxins and other toxic compounds including drugs. Promotes regeneration of the liver. Turmeric a cholagogue like dandelion, but may irritate the gastric mucosa. Its advantages are its cheapness and ability to be used in cookery. These herbs are best combined with wild yam, which helps to prevent liver spasms caused by gall bladder stimulating herbs. For help with a liver detoxification programme, it is best to consult a nutritional therapist, who can arrange for (non-invasive) tests to determine which pathways need boosting. For a list of nutritional therapists and other natural medicine practitioners in your area, send £1 plus sae to: Society for the Promotion of Nutritional Therapy (SPNT), PO Box 47, Heathfield, Glossaryacetylation – combination with acetic acid alveolar macrophages – rounded granular phagocyte cells in the alveoli of the lungs that ingest inhaled particulate matter aldehydes – a class of organic compounds containing the atomic group C(Carbon)H(Hydrogen)O(Oxygen) amines – organic compounds containing nitrogen amino acids – the chief constituents of proteins; the “building blocks” of life biochemical pathway – a series of chemical enzyme reactions, that converts one biological material into another Candida albicans – a quite common fungus in humans, which when unchecked can cause illness catalyse – speeding up of a chemical reaction by a substance which remains after the reaction conjugation – the joining together of two compounds to form another corpus luteum – a yellow glandular mass in the ovary dioxins – a group of chemicals present as trace contaminants in herbicides endogenous – arising from within the organism epoxides – compounds containing one oxygen atom bound to two different carbon atoms ethylene glycol – a solvent used as an antifreeze gall bladder – the reservoir for bile, on the surface of the liver hydrolysis – the splitting of a substance’s molecules by adding water (H 2 0): a hydrogen-oxygen molecule (HO-) being added to one fragment, and the hydrogen atom (H) to the other hydrophilic – readily interacting with water intracellular – within cells ketones – a class of organic compounds containing the molecule C=O lipids – fats and fat-like substances lipophilic – readily reacting with fat lymphocytes – an immune-system cell generated by lymph tissue metabolic, -ism – all the processes which create and maintain, and use up, organised living matter metabolites – any substance produced by metabolism methanol – a solvent methylation – the addition of a methyl, i.e. a molecule of C(Carbon) and three H(Hydrogen) atoms mitochondria – small cell organelles, with their own nucleic acids, that through synthesis of adenosine triphosphate (ATP) produce most of the energy for cells monocytes – cells formed in bone marrow that travel to tissues, e.g. lungs and liver, to develop into macrophages oxidation – the removal of electrons from the atoms of a substance; often by combination with oxygen pantothenic acid – a member of the vitamin B complex peptide – a compound of more than two amino acids peroxidation – a chemical reaction creating an oxide with more oxygen than any other polyunsaturated – denoting a chemical compound, particularly a fatty acid, having two or more double or triple bonds in its hydro-carbon chain reduction – the addition of electrons to the atoms of a substance; often by combination with hydrogen thiol – the univalient – S(sulphur)H(hydrogen) group vasculitis – inflammation of a (usually blood) vessel xenobiotics – substances foreign to the body |