The Liver and Detoxification

by Dr. Sandra Cabot

More than ever before in the history of mankind, human beings need to have healthy livers to break down the chemicals that have crept into our environment. If you talk to radiologists and gastroenterologists who are looking at people's livers today they will tell you that the condition "Fatty Liver" affects more than 50% of people over the age of 50!

Common causes are incorrect diet, excessive alcohol intake, adverse reactions to drugs and toxic chemicals, and viral hepatitis. Dr. Cabot believes it is because modern-day medicine has become sidetracked into treating the symptoms of diseases and not the causes. Excess weight is a symptom of liver dysfunction and not solely due to the number of calories you consume.

We have been attacking the symptoms of weight excess with fad diets, obsessional high impact aerobics, stomach stapling and toxic drugs, such as appetite suppressants, laxatives and diuretics. We have failed to consider the underlying cause of LIVER DYSFUNCTION and indeed we have virtually ignored the hardest-working organ in the body, with dire consequences.

Dr. Sandra Cabot's books on the liver show us these consequences - not just weight problems, but a higher incidence of cardiovascular and degenerative diseases that are the leading causes of death in modern affluent societies.

I received an E-mail from a reader of my books and websites, who was alarmed by the large number of hormone implants being inserted into beef animals where she worked in a stock and station agency. Steers are implanted with Hormonal Growth Promotants (HGP) which is justified by corporate statements, that tests have shown that a non-pregnant woman produces 54,000 times the amount of estrogen found in a 500 gram steak and that only a fraction of the amount used in human hormone replacement therapy is used in the implants that are put into animals. This is all very well, however, it is still increasing the workload of the liver, which over a long period of time may cause hormonal imbalances in those who eat beef regularly. We must ask ourselves why is the incidence of breast cancer so high, particularly in relatively young women? Surely it is better to eat meat from animals that roam free and happy in fresh green pastures that are not injected with potent hormones or fed concentrated stock feed to rush their growth?

The use of drugs to control and treat animal disease and to promote faster, more efficient growth of livestock is a common practice. An estimated 80 percent of U.S. livestock and poultry receive some animal drugs during their lifetime. Improper use of animal drugs may cause residues in the edible tissues of slaughtered animals that could be hazardous to consumers.

Most countries will have set MRL or Maximum Residue Limits. This is the amount of pesticide residue, heavy metals, hormone residues and natural toxins that the food ( eggs, meat or milk) are allowed to have and still be sold to the public for consumption. The MRL in Australia are set by the National Registration Authority for Agricultural and Veterinary Chemicals. In the USA they are set by authorities under the Food and Drug Administration. The key point is, just because a food substance complies in relation to the MRL , does not mean that the food is free from ALL contamination - just that it is at, or under, the level set by the particular authority deemed to be safe. MRLs are often set on a national basis to meet the requirements of a particular country. However, pests and pest pressure can vary between countries, as can chemicals used and agronomic practices. The lists of MRL values applying in different countries can therefore be quite different.

There is also the point that despite the existence of these laws, it does not guarantee that all farmers and growers comply 100% . Principle causes of excessive drug residues are failure to observe drug label withdrawal periods before slaughter or processing, or failure to withhold milk after dosing of herds with drugs such as the treatment of bovine mastitis with large doses of penicillin which requires a withholding period before the residues in milk are reduced to acceptable levels. Other causes may include failure to follow other drug label directions, poor feed manufacturing practices, and human negligence.

There are many chemicals (e.g., trace metals, industrial chemicals, and mycotoxins) that may be inadvertently present in animal tissues yet have no established safe concentrations. This of course does not mean that these substances are not harmful.

It is a fact of life that pesticides, herbicides and hormones are used in food production. Although the regulatory levels set by authorities provide some control over residues - it is not the 'be all and end all'. The liver is again highlighted as vital, as it is the organ that metabolizes these substances and excretes them from the body.

The liver is the gateway to the body and in this chemical age its detoxification systems are easily overloaded. Thousands of chemicals are added to food and over 700 have been identified in drinking water. Plants are sprayed with toxic chemicals, animals are injected with potent hormones and antibiotics and a significant amount of our food is genetically engineered, processed, refined, frozen and cooked. All this can lead to destruction of delicate vitamins and minerals, which are needed for the detoxification pathways in the liver. The liver must try to cope with every toxic chemical in our environment, as well as damaged fats that are present in processed and fried foods.

The Liver Filter

The liver is the cleanser and filter of the blood stream and is of vital importance. It is the largest organ in the body and has an enormous amount of blood flowing through it every minute of our lives. It is between 21 - 22.5 cm in its greatest diameter, 15 - 17.5cm in its greatest height and 10 - 12.5 cm in its depth, weighing around 1200 - 1600 gms

A Normal Healthy Liver

What are the functions of the liver?

• It is responsible for the production of bile which is stored in the gallbladder and released when required for the digestion of fats.
• The liver stores glucose in the form of glycogen which is converted back to glucose again when needed for energy.
• It also plays an important role in the metabolism of protein and fats. It stores the vitamins A, D, K, B12 and folate and synthesizes blood clotting factors.
• Another important role is as a detoxifier, breaking down or transforming substances like ammonia, metabolic waste, drugs, alcohol and chemicals, so that they can be excreted. These may also be referred to as "xenobiotic" chemicals. If we examine the liver under a microscope, we will see rows of liver cells separated by spaces which act like a filter or sieve, through which the blood stream flows. The liver filter is designed to remove toxic matter such as dead cells, microorganisms, chemicals, drugs and particulate debris from the blood stream. The liver filter is called the sinusoidal system, and contains specialized cells known as Kupffer cells which ingest and breakdown toxic matter.

The liver filter can remove a wide range of microorganisms such as bacteria, fungi, viruses and parasites from the blood stream, which is highly desirable, as we certainly do not want these dangerous things building up in the blood stream and invading the deeper parts of the body. Infections with parasites often come from the contaminated water supplies found in large cities, and indeed other dangerous organisms may find their way into your gut and blood stream from these sources. This can cause chronic infections and poor health, so it is important to protect your liver from overload with these microorganisms. The safest thing to do is boil your water for at least 5 minutes, or drink only bottled water that has been filtered and sterilized. High loads of unhealthy microorganisms can also come from eating foods that are prepared in conditions of poor hygiene by persons who are carrying bacteria, viruses or parasites on their skin. Foods, especially meats that are not fresh or are preserved, also contain a higher bacterial load, which will overwork the liver filter if they are eaten regularly.

Recently, it has become very fashionable for people to detoxify their bodies by various means, such as fasting or cleansing the bowels with fiber mixtures. Fasting can by its extreme nature, only be a temporary method of cleansing the body of waste products, and for many people causes an excessively rapid release of toxins which can cause unpleasant, acute symptoms. The liver filter, like any filter, needs to be cleansed regularly, and it is much easier and safer to do it everyday. This is easily and pleasantly achieved by adopting a daily eating pattern that maintains the liver filter in a healthy clean state. By following the methods and guidelines on this site, you will be able to keep the liver filter healthy and clean. Although it is important to keep the intestines moving regularly and to sweep their walls with high fiber and living foods, it is important to remember that the bowels are really a channel of elimination and not a cleansing organ per se. In other words the bowels cannot cleanse, filter or remove toxic wastes from the blood stream.

It is only the liver that can purify the blood stream and we only have one liver.

The Liver Detoxification Pathways

Inside 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 Substances

Basically 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 Pathway

An 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.

Phase Two - Detoxification Pathway

This 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 pathway

Salicylates 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 pathways

Neurotransmitters, steroid hormones, certain drugs such as Acetaminophen (also known as paracetamol) ,and many xenobiotic and phenolic compounds.

Substrates of glucuronidation

Polycyclic 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 Overload

If 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 1

1. Ross A. McKinnon and Michael E. McManus (1996). Localization of Cytochromes P450 in Human Tissues: Implications for Chemical Toxicity, Pathology, 28, 148 - 155.
2. Michael 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, Kristina 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 Peter 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 Peter 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, Chris 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 Johnston (1995). Effect of grapefruit juice on cyclosporin concentration, The Lancet, 346, 122-123.
11. Gary C Yee, Denise L Stanley, Lisa J Pessa, Teresa Dalla Costa, Susan E Beltz, Jorge Ruiz, David 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 Rodriguez-Lescure, E Diaz-Rubio, M Diaz-Rubio (1995). CYP2D6 genes and risk of liver cancer, The Lancet, 345, 830-831.
13. Agneta Rannug, PhD, Anna-Karin Alexandrie, 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. Daniel W. Nebert, David R. Nelson, Minor J. Coon, Ronald W. Eastbrook, Rene Feyereisen, Yoshiaki Fujii-Kuriyama, Frank J. Gonzalez, F. Peter Guengerich, Irwin C. Gunsalus, Eric F. Johnson, John C. Loper, Ryo Sato, Michael R. Waterman and David 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 Michael E. McManus (1996). Localisation of Cytochromes P450 in Human Tissues: Implications for Chemical Toxicity, Pathology, 28, 148-155.
17. Yan Li, Erija Wang, Chris 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, Mary 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. William D. Parsons, MD, and Allen H. Neims, MD., PhD. (1978). Effect of smoking on caffeine clearance, Clin Pharmacol Ther., 24/1, 40-45.
21. Steven N Lichtman, John Keku, John 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 II

1. Tory M. Hagen, Grazyna T. Wierzbicka, Barbara B. Bowman, Tak Yee Aw, and Dean P. Jones (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. Smith (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, Christine E. Szarka, Gordon R. Pfeiffer, Todd A. Graham, Andrew M. Balshem, Samuel Litwin, Eric B. Goosenberg, Harold Frucht, and Paul F. Engstrom (1997). Preclinical and Clinical Evaluation of Broccoli Supplements as Inducers of Glutathione S-Transferase Activity, Clinical Cancer Research, 3, 25-30.
5. Sonia M. F. De Morais, Jack P. Uetrecht, and Peter G. Wells (1992). Decreased Glucoronidation and Increased Bioactivation of Acetaminophen in Gilbert's Syndrome, Gastroenterology, 102, 577-586.
6. M Thomas Heafield, Simon Fearn, Glyn B. Steventon, Rosemary H. Waring, Adrian C. Williams and Steven 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. Marion 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. Elizabeth A. Offord, Katherine Mace, Ornella Avanti, Andrea 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, Jonathan A C Sterne, Christina E Songhurst, Peter G J Burney (2000). Frequent paracetamol use and asthma in adults, Thorax, 55, 266-270.
12. Chandradhar Dwivedi, Wendy J. Heck, Alan A. Downie, Saroj Larroya, and Thomas 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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