STEP PERSPECTIVE, Volume 8, No. 3 - Winter/1996; A Publication of the Seattle Treatment Exchange Project e-mail: step@eskimo.com
Brad S. Lichtenstein, ND

One of the key roles of the liver is detoxification. Detoxification is the process of neutralizing and eliminating toxins from the body. External sources of toxins include smoke, fumes, pesticides, drugs, pathogenic microorganisms, food additives and dyes, and excessive hormones found in animal products. Oddly, our body generates its own source of internal toxins during the detoxification process. For this reason, maximum liver function must be maintained in order to prevent destruction of liver cells (hepatocytes) and other bodily tissues. The liver deals with toxins in a variety of ways. In the healthy, optimally functioning liver, approximately two liters ( half a gallon) of blood flow through it each minute before returning to general circulation. While in the liver the hepatocytes filter out toxins and bacteria. Special liver cells, called Kupffer cells, engulf foreign particles (bacteria and toxins), ingest them, and remove them from the bloodstream. This filtration is the first step in the detoxification process.

The second step occurs during the liver's daily production of bile. Bile is necessary for digestion and absorption of all fats. This includes the fat soluble vitamins, vitamins A, K, E, and O. Without bile, deficiencies in the fat soluble antioxidants (vitamins A, K, E and 0) would ensue. For detoxification purposes, toxins in the liver bind to bile to be excreted from the body. Fiber, from the diet, is necessary in order for this toxic bile to be excreted through the feces. If bile, or fiber for that matter, is not present, these toxins will become reabsorbed in the intestines and re-enter the bloodstream, allowing them another chance at destruction. The last step in the detoxification process involves a series of enzyme systems which help remove chemicals from the bloodstream by neutralizing them. The two pathways required in this operation are known as the Phase I and Phase II detoxification systems. Phase I directly alters the structure of chemical compounds. This initial phase involves a series of enzymes collectively known as the mixed function oxidase system (MFOS0, which includes approximately 100 different enzymes perform the following role during Phase I detoxification:

* Activate chemicals, drugs and foods into substances the body can use.

* Inactivate toxic and carcinogenic (cancer causing) chemicals and drugs by making them water soluble and thus able to be safely excreted from the body through the kidneys.

* Activate chemicals and drugs which are basically harmless until they pass through these enzyme systems and are converted into toxins and carcinogens.

When this last step occurs, a new chemical intermediate is formed that is more toxic than the original substance. Smoking is an example of this process. When the chemicals from tobacco or charcoaled foods (polycyclic hydrocarbons) are taken into the body, they are not carcinogenic until they pass through Phase I detoxification. The intermediates formed during this process are more chemically toxic than the original substance. On an unfortunate note, every time the Phase I system is invoked, free radicals are generated which can, in turn, produce more free radicals and result in serious injury and stress to the body. Therefore, despite the perceived benefits of Phase I detoxification, activation of the system is not always desired, as we will discuss below.

The body deals with the intermediates of Phase I by shuttling them to Phase II. In Phase II, another group of enzymes, the conjugating enzymes, are involved. Not only do these enzymes conjugate (attach particles) to the intermediates, (which inactivates them in order to be safely excreted in urine or bile), but they may also conjugate chemicals which never passed through Phase I. In order to deal effectively with toxins, the Phase II system must be kept working properly. If Phase I is working well, yet Phase II is not, build up and the Phase I induced, chemically altered, toxic intermediates will have no means of being removed from the body. They will continue to circulate in the blood stream causing more damage. Ritonavir affects the liver's ability to perform optimally. Ritonavir affects the MFOS by keeping the cP450 enzymes busy and unavailable. In other words, ritonavir inactivates the cP450 enzymes. As a result, many drug interactions can occur when taking this protease inhibitor. First, the liver's ability to clear drugs such as antihistamines and benzodiazepine antidepressants can pose life-threatening complications when taken in conjunction with ritonavir. The majority of drugs taken orally undergo a process known as the "first pass effects." This process occurs when the drug enters the bloodstream and goes to the liver to be metabolized, or inactivated, by the cP450 enzymes. The dosages for oral medications take this into consideration. Since ritonavir ties up the enzymes essential for this to occur, chemicals and drugs are unable to be metabolized properly. Therefore, they stay in the bloodstream longer and at higher concentrations. What was once a standard dose now becomes a toxic one, since they are not fully inactivated by the liver.

Second, ritonavir affects the liver's ability to activate many chemicals and drugs in order for them to be converted into substances the body can use. This is the reason why many drugs lose their effectiveness in conjunction with ritonavir; oral birth control pills are an example of this. Since these drugs need to be converted by the c P540 enzymes, an increased dose is necessary in order to obtain the desired effects.

Diet and food can play a role in influencing the liver and the Phase I and Phase II detoxification systems. Although no studies exist as of this date regarding the interaction between food and ritonavir, much has been written describing the role of diet and lifestyle on basic drug metabolism. Once again, we find that common sense and basic nutrition cannot be overlooked when the goal is to stimulate the body's natural ability to stay healthy and maintain a strong functioning immune system.

The goal for healing with food is to ensure that Phase II detoxification is working properly. Although the cP450 system (Phase I) is inactivated by ritonavir, attempts at activating these enzymes is not necessarily the objective. By activating these enzymes, we decrease the effectiveness and concentration of ritonavir in the body. This is seen in tobacco smoke. Tobacco and other smoked products contain chemicals (nitrosamines) which must be activated by the cP540 enzymes in order for their toxic and carcinogenic effects to take place in the body, i.e., they must be converted to toxic intermediates. These nitrosamines activate the cP450 enzymes. The same thing occurs with charcoaled food which yields polycyclic hydrocarbons. Theses hydrocarbons are produced by incomplete combustion when drippings contact hot coals and are redeposited on the foods. Hydrocarbons activate cP450 enzymes as well. Studies show that those who smoke have an 18% reduction in their blood levels of ritonavir. This is due to the fact that activated cP450 enzymes begin clearing ritonavir from the body. Alcohol also increases the cP450 activity and may have the same effects on blood levels of this drug as does tobacco. Stimulating cP450 enzymes has another hazard; activating Phase I detoxification without an intact Phase II can result in an increase in circulating toxic intermediates which can be life-threatening.

In addition to these effects, both smoking and alcohol consumption lead to deficiencies in nutrients essential for virtually all enzymatic pathways in the body, especially Phase II detoxification. The consequences of such deficiencies can be more problematic for maintaining a healthy immune system and functioning liver that the actual activation of cP450 enzymes. Therefore, as a rule, avoidance of tobacco, alcohol and charcoaled foods is advisable. If cooking with charcoal, tightly wrap foods in aluminum foil in order to prevent the formation of hydrocarbons.

As mentioned above, adequate nutrition is paramount. In order for the Phase II detoxification to perform optimally, it must have all the basic building blocks. The proper vitamins and minerals must be available; without them, detoxification cannot occur. Vitamin deficiencies can lead to an increased conversion of procarcinogenic substances to toxins and carcinogens by the cP450 system, and an increased level of circulating toxic intermediates from Phase I. Providing the body with the essential nutrients, either through supplementation, or diet, helps restore balance. All the B vitamins, (thiamin, riboflavin, niacin, pantothenic acid pyridoxine, folic acid and cobalamin), are needed at some level for the Phase II system to function properly. Emphasis should be given to these nutrients of the antioxidant family as well, namely vitamin C and E, beta carotene and selenium. Both vitamin C and E can block the formation of nitrosamines which can prevent activation of cP450 enzymes and inhibit tumor formation. Furthermore, when levels of selenium and B vitamins decrease, glutathione decreases. Glutathione is a major antioxidant in both of the Phase I and Phase II systems. Stores of glutathione must be maintained to prevent free radical damage and ensure adequate detoxification. The amino acid N-acetylcysteine (NAC) can protect glutathione levels from dropping in the body. NAC supplementation has been studied for its ability to successfully treat and prevent liver toxicity by such drugs as acetaminophen (Tylenol). All in all, supplementation with a good multivitamin is a start and can ensue the body with B vitamins, antioxidants and NAC is warranted when taking ritonavir. However, supplementation does not preclude the fundamental necessity for proper diet. Like the effects of tobacco and alcohol, methylxanthines, such as caffeine, theophylline, and cola induce the cP450 enzymes of Phase I. Rather than further stimulate this system, it would be best to decrease consumption of foods containing theses substance. Such foods would include coffee, black teas, chocolate, and sodas. As with all parts of our lives, balance is the key; complete avoidance to the point of fanaticism is not necessary. If you are taking a protease inhibitor, rather than continue to stress the liver, allow it time to balance and recharge. Although these protease inhibitors are extremely potent, becoming obsessed with everything you do (including everything you eat and drink) does not promote healing and wellness. If you find yourself drinking many cups of coffee per day, explore your need for coffee. If you find yourself addicted to the caffeine, now would be and excellent time to do something about it. This does not mean coffee can never be consumed again. It simply suggests that moderation, without addiction, is key.

Cruciferous vegetables, such as broccoli, cabbage, and brussel sprouts, contain a chemical known as indole-3-carbinol which is a potent activator of Phase I and Phase II detoxification. While diets high in these vegetables have anti-tumor producing effects, they induce cP450 enzymes. Remember activation of Phase I is problematic with out Phase II. Since cruciferous vegetables do both, simply be cautious. Even though your mother may have had good motives, feel comforted in knowing that it is not always beneficial to eat your brussel sprouts! So what to eat or drink? One class of chemical compounds, flavonoids, phenolic compounds abundant in fruits and vegetable, have potent action on Phase I and Phase II systems. Not all flavonoids are the same. Flavonoids containing multiple hydroxyl groups appear to be more effective inhibitors. Fruits such as lemons, limes, and grapefruits possess the highest amounts of these polyhydroxylated flavonoids, while tangerines and oranges do not. Ingestion of lemons, limes, and grapefruits inactivate Phase I even more. Since ritonavir is already performing this action, there is no need to provoke the situation any further. Oranges and tangerines, on the other hand , activate Phase I, which we do not want to do either. As a rule, avoidance of citrus fruits and juices is wise. The inhibition of Phase I detoxification is the reason why people are told to take their saquinivir (invirase) with an 8 once glass of grapefruit juice. If the cP450 enzymes are inactivated, then the drug (saquinivir) will not be cleared from the system as readily. Ritonavir's inhibition of cP450 enzymes is the rationale behind taking both of these protease inhibitors simultaneously. Ritonavir will increase circulating saquinivir in the bloodstream. Unfortunately, without an understanding of proper dosage, this combination can be lethal. Studies are being conducted to determine the levels and concentration necessary for these two drugs to be taken together.

Consuming the following foods daily would be helpful to ensure proper Phase II detoxification; foods high in glutathione, sulfur containing amino acids, protein, and vitamins, especially B and C. Glutathione rich foods include asparagus, walnuts and avocados. Foods high in sulfur containing amino acids include red peppers, onions and garlic, and cruciferous vegetables (to be eaten moderately). Some foods with B vitamins are yeast, whole grains, animal products and beans. Vitamin C are peppers and cabbage. Again, supplementation is useful to ensure no deficiencies are occurring. Yet, supplementation should never be used as a means of ignoring healthy eating habits.

Included in a healthy diet for the liver would be herbs and vegetables that are known to stimulate liver detoxification and cleansing. Such vegetables that are known to stimulate liver detoxification and cleansing. Such vegetables are beets, artichokes, radishes, carrots and baby dandelion greens. As a rule of thumb, dark leafy green and yellow vegetables have healing properties for the liver and should be consumed often. Licorice root contains the chemical compound glycyrrthitinic acid which accords protection for the liver. Licorice prevents destruction of the liver cells by toxins, decreases the production of free radicals and helps restore balance to the adrenal glands (helping those suffering from fatigue due to over exertion and stress). This herb can be added to the diet through teas made from the fresh root. A word of warning: Licorice root should not be used by those with pre-existing condition of hypertension as glycyrrhitinic acid is known to exacerbate this condition. Glycyrrhitinic acid does not raise the blood pressure of those individuals with normal levels. Deglycyrrhinated licorice root (DGL), however, does not provide the benefits for the liver listed above, and therefore should not be used with these goals in mind. The herb milk thistle (silybum marianum) contains the chemical silymarin which has been studied for its many healthy effects of the liver. Milk thistle is known to prevent liver cell destruction, enhance liver function, inhibit free radical damage in the liver, inhibit synthesis of inflammatory chemicals (prostaglandins) and promote protein synthesis of new liver cells. Studies have demonstrated milk thistle's ability to prevent liver necrosis (destruction of liver cells) from toxic chemicals, such as carbon tetrachloride, when administered intravenously. On the whole, adding milk thistle to your daily regime can have a major effect in preserving your liver cells and minimizing the toxic effects of many medications in addition to ritonavir. Milk thistle can be found in capsules as well as the seeds. If using capsules or tincture, look for standardized extract with at least 70% silymarin content. When using the seeds, these can be soaked in water or apple juice overnight, then crushed or blended in order to be consumed.

Drug therapy, regardless of its benefits, can be harsh on the body, especially the liver. Taking steps towards healing requires an examination of our behaviors, including our eating habits. Avoiding known carcinogens and stimulators of the MFOS, (smoking, alcohol, and charcoal foods), will only promote our well-being and health. The choices we make in our diets can positively affect our liver. Supplementation with antioxidants and B vitamins supports Phase II detoxification system. Adequate fiber in the diet ensures that toxins in the bile are removed effectively. As a basic rule, a diet high in fresh vegetables and fruits (particularly yellow-green vegetables and fruits),and whole grains has a protective affect on the liver. The goal is balance.

About The Author

Dr. Brad S. Lichtenstein is a licensed naturopathic physician in private practice in Seattle and is a member of STEP's Scientific Review Committee.

Bibliography

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These articles were provided by the Seattle Treatment Education Project - Copyright (c) 1997 - Seattle Treatment Education Project. Noncommercial reproduction encouraged. Distributed by AEGIS - http://www.aegis.com
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Copyright © 1996 - Seattle Treatment Education Project (STEP) - All rights reserved. Noncommercial reproduction is encouraged. STEP is published four times a year by the Seattle Treatment Education Project, 127 Broadway East, 3rd Floor, Seattle, WA 98102.    Email: step100@aol.com  STEP web page