The Liver Detoxification Pathways

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Pretty diag of the liver and detox pathways at link

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http://www.liverdoctor.com/03_detoxpathways.asp

The Liver Detoxification PathwaysInside the liver cells there are sophisticated mechanisms that have evolved over millions of years to break down toxic substances. Every drug, artificial chemical, pesticide and hormone, is broken down (metabolized) by enzyme pathways inside the liver cells. Many of the toxic chemicals that enter the body are fat-soluble, which means they dissolve only in fatty or oily solutions and not in water. This makes them difficult for the body to excrete. Fat soluble chemicals have a high affinity for fat tissues and cell membranes, which are made of fatty substances. In these fatty parts of the body, toxins may be stored for years, being released during times of exercise, stress or fasting. During the release of these toxins, symptoms such as headaches, poor memory, stomach pain, nausea, fatigue, dizziness and palpitations may occur.

The body's primary defense against metabolic poisoning is carried out by the liver. The liver has two mechanisms designed to convert fat-soluble chemicals into water soluble chemicals so that they may then be easily excreted from the body via watery fluids such as bile and urine.

How the Liver Detoxifies Harmful SubstancesBasically there are TWO major detoxification pathways inside the liver cells, which are called the Phase 1 and Phase 2 detoxification pathways.

Toxin list: metabolic end products, micro organisms, contaminants/pollutants, insecticides, pesticides, food additives, drugs, alcohol.

Phase One - Detoxification PathwayAn example of the phase one pathway is the Cytochrome P-450 mixed function oxidase enzyme pathway. These enzymes reside on the membrane system of the liver cells (called Hepatocytes).

Human liver cells possess the genetic code for many isoenzymes of P-450 whose synthesis can be induced upon exposure to specific chemicals. This provides a mechanism of protection from a wide variety of toxic chemicals.

To put it simply, this pathway converts a toxic chemical into a less harmful chemical. This is achieved by various chemical reactions (such as oxidation, reduction and hydrolysis), and during this process free radicals are produced which, if excessive, can damage the liver cells. Antioxidants (such as vitamin C and E and natural carotenoids) reduce the damage caused by these free radicals. If antioxidants are lacking and toxin exposure is high, toxic chemicals become far more dangerous. Some may be converted from relatively harmless substances into potentially carcinogenic substances.

Excessive amounts of toxic chemicals such as pesticides can disrupt the P-450 enzyme system by causing over activity or what is called 'induction' of this pathway. This will result in high levels of damaging free radicals being produced.

Substances that may cause overactivity (or induction) of the P- 450 enzymes:Caffeine, Alcohol, Dioxin, Saturated fats, Organophosphorus pesticides, Paint fumes, Sulfonamides, Exhaust fumes, Barbiturates

The family of P-450 enzyme systems is quite diverse, with specific enzyme systems being inducible by particular drugs, toxins or metabolites. It is this characteristic that has allowed the development of special tests to check the function of the various pathways - see liver tests. The substrate is the substance that is acted upon by the enzyme.

Substrates of cytochrome P-450 enzymes:

Theophylline, caffeine, phenacetin, acetaminophen, Lidocaine, erythromycin, cyclosporin, ketoconazole, testosterone, estradiol, cortisone, Alprenolol, bopindolol, carvedilol, metoprolol, propranolol , Amitriptyline, clomipramine, desipramine, nortriptyline , Codeine, dextrometh- orphan, ethylmorphine, 4-methoxyamphetamin Family Phenytoin, ibuprofen, naproxen, oxicam drugs, S-warfarin, epam, hexobarbitone, imipramine, omeprazole, alcohol, chlorzoxazone, enflurane.

Phase Two - Detoxification PathwayThis is called the conjugation pathway, whereby the liver cells add another substance (eg. cysteine, glycine or a sulphur molecule) to a toxic chemical or drug, to render it less harmful. This makes the toxin or drug water-soluble, so it can then be excreted from the body via watery fluids such as bile or urine.

Major Phase II pathways include glutathione, sulfate, glycine, and glucuronide conjugations. Individual xenobiotics and metabolites usually follow one or two distinct pathways. Again, this makes testing of the various pathways possible by challenging with known substances.

The conjugation molecules are acted upon by specific enzymes to catalyse the reaction step. Through conjugation, the liver is able to turn drugs, hormones and various toxins into excretable substances. For efficient phase two detoxification, the liver cells require sulphur-containing amino acids such as taurine and cysteine. The nutrients glycine, glutamine, choline and inositol are also required for efficient phase two detoxification. Eggs and cruciferous vegetables (eg. broccoli, cabbage, Brussels sprouts, cauliflower), and raw garlic, onions, leeks and shallots are all good sources of natural sulphur compounds to enhance phase two detoxification. Thus, these foods can be considered to have a cleansing action. The phase two enzyme systems include both UDP-glucuronyl transferase (GT) and glutathione-S-transferase (GSH-T). Glutathione is the most powerful internal antioxidant and liver protector. It can be depleted by large amounts of toxins and/or drugs passing through the liver, as well as starvation or fasting. Phase II reactions may follow Phase I for some molecules or act directly on the toxin or metabolite.

Substrates of the glycine pathwaySalicylates and benzoate are detoxified primarily through glycination. Benzoate is present in many food substances and is widely used as a food preservative. Many other substances are detoxified as well via the glycine conjugation pathway. Patients suffering from xenobiotic overloads and environmental toxicity may not have sufficient amounts of glycine to cope with the amount of toxins they are carrying.

Substrates of the sulfation pathwaysNeurotransmitters, steroid hormones, certain drugs such as Acetaminophen (also known as paracetamol) ,and many xenobiotic and phenolic compounds.

Substrates of glucuronidationPolycyclic aromatic hydrocarbons, steroid hormones, some nitrosamines, heterocyclic amines, some fungal toxins, and aromatic amines. It also removes "used" hormones, such as estrogen and T4 (thyroid hormone) that are produced naturally by the body.

Toxic OverloadIf the phase one and two detoxification pathways become overloaded, there will be a build up of toxins in the body. Many of these toxins are fat soluble and incorporate themselves into fatty parts of the body where they may stay for years, if not for a lifetime. The brain and the endocrine (hormonal) glands are fatty organs, and are common sites for fat-soluble toxins to accumulate. This may result in symptoms of brain dysfunction and hormonal imbalances, such as infertility, breast pain, menstrual disturbances, adrenal gland exhaustion and early menopause. Many of these chemicals (eg. pesticides, petrochemicals) are carcinogenic and have been implicated in the rising incidence of many cancers.

Rarely does anyone think about the liver, which seems incredible to me because it is such a powerful organ and is easily improved. Indeed the simplest and most effective way to cleanse the blood stream and thus take the load off the immune system is by improving liver function.

LIVER REFERENCES - PHASE 11. Ross A. McKinnon and E. McManus (1996). Localization of Cytochromes P450 in Human Tissues: Implications for Chemical Toxicity, Pathology, 28, 148 - 155. 2. Murray and Gordon F. Reidy (1990). Selectivity in the Inhibition of Mammalian Cytochromes P450 by Chemical Agents, Pharmacological Reviews, 42/2, 85 -101. 3. Uwe Fuhr, a Klittich & A. Horst Staib (1993). Inhibitory effect of grapefruit juice and its bitter principle, naringenin, on CYP1A2 dependant metabolism of caffeine in man. 4. MA Kall and J Clausen (1995). Dietary effect of mixed function P450 1A2 activity assayed by estimation of caffeine metabolism in man, Human & Experimental Toxicology, 14, 801 - 807. 5. F Guengerich (1995). Influence of nutrients and other dietary materials on cytochrome P-450 enzymes, Am J Clin Nutr, 61 (suppl), 651S - 8S. 6. Karl Ludwig Rost, MD, and Ivar Roots, MD (1993). Accelerated caffeine metabolism after omeprazole treatment is indicated by urinary metabolite ratios: Coincidence with plasma clearance and breath test, Clinical Pharmacology & Therapeutics, 55/4, 402-411. 7. F Guengerich (1995). Influence of nutrients and other dietary materials on cytochrome P-450 enzymes, AM J Clin Nutr, 61(suppl), 651S-8S. 8. Yan Li, Erija Wang, J. Patten, Laishun Chen, and Chung S. Yang (1994). Effects of Flavonoids on Cytochrome P450-Dependent Acetamophen Metabolism in Rats and Human Liver Microsomes, Drug Metabolism and Disposition, 22/4, 565-571. 9. Werner Kalow, MD and Bing-Kou Tang, PhD (1991). Caffeine as a metabolic probe: Exploration of the enzyme-inducing effect of cigarette smpking, Clin Pharmacol Ther, 49/1, 44-48. 10. Atholl ston (1995). Effect of grapefruit juice on cyclosporin concentration, The Lancet, 346, 122-123. 11. C Yee, L Stanley, J Pessa, Dalla Costa, E Beltz, Ruiz, T Lowenthal (1995). Effect of grapefruit juice on cyclosporin concentration, The Lancet, 345, 955-956. 12. J A G Agundez, M C Ledesma, Prof J Benitez, J M Ladero, A -Lescure, E -Rubio, M -Rubio (1995). CYP2D6 genes and risk of liver cancer, The Lancet, 345, 830-831. 13. Agneta Rannug, PhD, -Karin andrie, BSc, Irene Persson, BSc, Magnus Ingelman-Sundberg, PhD, BScM (1995). Genetic Polymorphism of Cytochromes P450 1A1, 2D and 2E1: Regulation and Toxicological Significance, JOEM, 37/1, 25-36. 14. W. Nebert, R. , Minor J. Coon, W. Eastbrook, Rene Feyereisen, Yoshiaki Fujii-Kuriyama, J. , F. Guengerich, Irwin C. Gunsalus, F. , C. Loper, Ryo Sato, R. Waterman and Waxman (1991). The P450 Superfamily: Update on New Sequences, Gene Mapping, and Recommended Nomenclature, DNA and Cell Biology, 10/1, 1-14. 15. Brent A. Neuschwander-Tetri, MD (1995). Common blood tests for liver disease. Which ones are most useful? Postgraduate Medicine, 98/1, 49-63. 16. Ross A. McKinnon and E. McManus (1996). Localisation of Cytochromes P450 in Human Tissues: Implications for Chemical Toxicity, Pathology, 28, 148-155. 17. Yan Li, Erija Wang, J. Patten, Laishun Chen, and Chung S. Yang (1994). Effects of Flavonoids on Cytochrome P450-Dependant Acetaminophen Metabolism in Rats and Human Liver Microsomes, Drug Metabolism and Disposition, 22/4, 566-571. 18. Nathalie Roland, Lionelle Nugon-Baudon, Jean-Pierre Flinois and Philippe Beaune (1994). Hepatic and Intestinal Cytochrome P-450 Glutathione-S-Transferase and UDP-Glucuronosyl Transferase Are Affected by Six Types of Dietary Fibre in Rats Inoculated with Human Whole Fecal Flora, J Nutr., 124, 1581-1587. 19. K. D. R. Setchell, Beth Welsh, Marquelle J. Klooster and W. F. Balistreri (1987). Rapid High-Performance Liquid Chromatography Assay for Salivary and Serum Caffeine Following an Oral Load, Journal of Chromatography, 385, 267-274. 20. D. Parsons, MD, and H. Neims, MD., PhD. (1978). Effect of smoking on caffeine clearance, Clin Pharmacol Ther., 24/1, 40-45. 21. N Lichtman, Keku, H. Schwab, and R. Balfour Sartor (1991). Hepatic Injury Associated With Small Bowel Bacterial Overgrowth in Rats Is Prevented by Metronidazole and Tetracycline, Gastroenterology, 100, 513-519.

LIVER REFERENCES: PHASE II1. Tory M. Hagen, Grazyna T. Wierzbicka, Barbara B. Bowman, Tak Yee Aw, and Dean P. (1990). Fate of dietary glutathione: disposition in the gastrointestinal tract, Am J. Nutr., 259, G530-G535. 2. A. J. Hutt, J. Caldwell and R. L. (1986). The metabolism of aspirin in man: a population study, Xenobiotica, 16/3, 239-249. 3. Gerhard Levy (1986). Sulfate conjugation in drug metabolism: role of inorganic sulfate, Federation Proceedings, 45/8, 2235-2240. 4. Margie L. Clapper, E. Szarka, Gordon R. Pfeiffer, Todd A. Graham, M. Balshem, Litwin, B. Goosenberg, Harold Frucht, and F. Engstrom (1997). Preclinical and Clinical Evaluation of Broccoli Supplements as Inducers of Glutathione S-Transferase Activity, Clinical Cancer Research, 3, 25-30. 5. M. F. De Morais, Jack P. Uetrecht, and G. Wells (1992). Decreased Glucoronidation and Increased Bioactivation of Acetaminophen in Gilbert's Syndrome, Gastroenterology, 102, 577-586. 6. M Heafield, Simon Fearn, Glyn B. ton, Rosemary H. Waring, C. and G. Sturman (1990). Plasma cysteine and sulphate levels in patients with Motor neurone, Parkinson's and Alzheimer's disease, Neuroscience Letters, 110, 216-220. 7. A. Temellini, S. Mogavero, P.C. Giulianotti, A. Pietrabissa, F. Mosca and G. Pacifici (1993). Conjugation of benzoic acid with glycine in human liver and kidney: a study on the interindividual variability, Xenobiotica, 23/12, 1427-1433. 8. M. M. Reicks and D. Crankshaw (1993). Effects of D-limonene on hepatic microsomal monooxygenase activity and paracetamol-induced glutathione depletion in mouse, Xenobiotica, 23/7, 809-819. 9. n Man-Ying Chan, Chi-Tang Ho, Hsing-I Huang (1995). Effects of three dietary phytochemicals from tea, rosemary and turmeric on inflammation-induced nitrite production, Cancer Letters, 96, 23-29. 10. A. Offord, Mace, Ornella Avanti, M. A. Pfeifer (114). Mechanisms involved in the chemoreceptive effects of rosemary extract studied in human liver and bronchial cells, Cancer Letters, 114, 275-281. 11. Seif O Shaheen, A C Sterne, E Songhurst, G J Burney (2000). Frequent paracetamol use and asthma in adults, Thorax, 55, 266-270. 12. Chandradhar Dwivedi, J. Heck, Alan A. Downie, Saroj Larroya, and E. Webb (1990). Effect of Calcium Glucarate on ß-Glucoronidase Activity and Glucarate Content of Certain Vegetables and Fruits, Biochemical Medicine and Metabolic Biology, 43, 83-92.

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