One of the liver’s primary functions is filtering the blood. Almost 2 quarts of blood pass through the liver every minute for detoxification. Filtration of toxins is absolutely critical as the blood from the intestines contains high levels of bacteria, bacterial endotoxins, antigen–antibody complexes, and various other toxic substances. When working properly, the liver clears 99% of the bacteria and other toxins during the first pass. However, when the liver is damaged, such as in alcoholics, the passage of toxins increases by over a factor of 10.
The liver’s second detoxification process involves the synthesis and secretion of bile. Each day the liver manufactures approximately 1 quart of bile, which serves as a carrier in which many toxic substances are dumped into the intestines. In the intestines, the bile and its toxic load are absorbed by fiber and excreted. However, a diet low in fiber results in inadequate binding and reabsorption of the toxins. This problem is magnified when bacteria in the intestine modify these toxins to more damaging forms.
Phase I detoxification
The liver’s third role in detoxification typically involves a two-step enzymatic process for the neutralization of unwanted chemical compounds ( Table 50.3 ). These not only include drugs, pesticides, and toxins from the gut, but also normal body chemicals such as hormones and inflammatory chemicals (e.g. histamine) which become toxic if allowed to build up. Phase I enzymes directly neutralize some chemicals, but most are converted to intermediate forms that are then processed by phase II enzymes. These intermediate forms are much more chemically active and therefore more toxic. If the phase II detoxification systems are not working adequately, these intermediates can cause substantial damage, including the initiation of carcinogenic processes.
Phase I detoxification of most chemical toxins involves a group of enzymes which, collectively, have been named cytochrome P450. Some 50–100 enzymes make up the
cytochrome P450 system. Each enzyme works best in detoxifying certain types of chemicals, but with considerable overlap in activity among the enzymes.
The activity of the various cytochrome P450 enzymes varies significantly from one individual to another, based on genetics, the individual’s level of exposure to chemical toxins, and his or her nutritional status. Since the activity of cytochrome P450 varies so much, so does an individual’s risk for various diseases. For example, as highlighted in the study of chemical plant workers in Turin discussed above, those with underactive cytochrome P450 are more susceptible to cancer. This variability of cytochrome P450 enzymes is also seen in the variability of people’s ability to detoxify the carcinogens found in cigarette smoke and helps to explain why some people can smoke with only modest damage to their lungs, while others develop lung cancer after only a few decades of smoking.
Patients with underactive phase I detoxification will experience caffeine intolerance, intolerance to perfumes and other environmental chemicals, and an increased risk for liver disease, while those with an overactive system will be relatively unaffected by caffeine drinks. One way of objectively determining the activity of phase I is to measure how efficiently a person detoxifies caffeine. Using this test, a surprising fivefold difference in the detoxification rates of apparently healthy adults has been discovered.
When cytochrome P450 metabolizes a toxin, it chemically transforms it to a less toxic form, makes it water-soluble, or converts it to a more chemically active form. Caffeine is an example of a chemical directly neutralized by phase I. Making a toxin water-soluble allows its ex-cretion by the kidneys. Transforming a toxin to a more chemically reactive form makes it more easily metabolized by the phase II enzymes.
A significant side-effect of phase I detoxification is the production of free radicals as the toxins are transformed – for each molecule of toxin metabolized by phase I, one molecule of free radical is generated. Without adequate free radical defenses, every time the liver neutralizes a toxin exposure, it is damaged by the free radicals produced.
The most important antioxidant for neutralizing the free radicals produced in phase I is glutathione. In the process of neutralizing free radicals, however, glutathione (GSH) is oxidized to glutathione disulfide (GSSG). Glutathione is required for one of the key phase II detoxification processes. When high levels of toxin exposure produce so many free radicals from phase I detoxification that the glutathione is depleted, the phase II processes dependent upon glutathione stop.
Another potential problem occurs because the toxins transformed into activated intermediates by phase I are substantially more reactive. Unless quickly removed from the body by phase II detoxification mechanisms,
they can cause widespread problems, especially carcinogenesis. Therefore, the rate at which phase I produces activated intermediates must be balanced by the rate at which phase II finishes their processing. People with a very active phase I detoxification system coupled with slow or inactive phase II enzymes are termed “pathological detoxifiers”. These people suffer unusually severe toxic reactions to environmental poisons.
An imbalance between phase I and phase II can also occur when a person is exposed to large amounts of toxins or exposed to toxins for a long period of time. In these situations, the critical nutrients needed for phase II detoxification are depleted, which allows the highly toxic activated intermediates to build up.
Recent research shows that the cytochrome P450 enzyme systems are also found in other parts of the body, especially the brain cells. Inadequate antioxidants and nutrients in the brain result in an increased rate of neuron damage, such as seen in Alzheimer’s and Parkinson’s disease patients.
As with all enzymes, the cytochrome P450s require several nutrients, listed in Table 50.4 , in order to function.
A considerable amount of research has found that
TABLE 50-4-- Nutrients needed by phase I detoxification
• Magnesium (deficiency substantially increases toxicity of many drugs)
• Vitamin C
TABLE 50-5-- Substances that activate phase I detoxification
• Nicotine in cigarette smoke
• Cabbage, broccoli, and brussels sprouts
• Charcoal-broiled meats (due to their high levels of toxic compounds)
• Toxins from inappropriate bacteria in the intestines
various substances activate cytochrome P450 (see Table 50.5 ) while other substances inhibit it (see Table 50.6 ).
Inducers of phase I detoxification
Cytochrome P450 is induced by some toxins and by some foods and nutrients. Obviously, it is beneficial to improve phase I detoxification in order to eliminate toxins as soon as possible. This is best accomplished by providing the needed nutrients and non-toxic stimulants while avoiding those substances that are toxic. However, stimulation of phase I is contraindicated if the patient’s phase II systems are underactive.
All of the drugs and environmental toxins listed in Table 50.5 activate P450 to combat their destructive effects, and in so doing, not only use up compounds needed for this detoxification system but contribute significantly to free radical formation and oxidative stress.
Among foods, the brassica family, i.e. cabbage, broccoli, and brussels sprouts, contains chemical constituents that stimulate both phase I and phase II detoxification enzymes. One such compound is indole-3-carbinol, which is also a powerful anti-cancer chemical. It is a very active stimulant of detoxifying enzymes in the gut as well as the liver. The net result is significant protection against several toxins, especially carcinogens. This helps to explain why consumption of cabbage family vegetables protects against cancer.
Oranges and tangerines (as well as the seeds of caraway and dill) contain limonene, a phytochemical that has been found to prevent and even treat cancer in animal models. Limonene’s protective effects are probably due to the fact that it is a strong inducer of both phase I and phase II detoxification enzymes that neutralize carcinogens.
Inhibitors of phase I detoxification
Many substances inhibit cytochrome P450. This situation can cause substantial problems as it makes toxins potentially more damaging because they remain in the body longer before detoxification. For example, grapefruit juice decreases the rate of elimination of drugs from the blood and has been found to substantially alter their clinical activity and toxicity. Eight ounces of grapefruit juice contains enough of the flavonoid naringenin to decrease cytochrome P450 activity by a remarkable 30%. The common inhibitors of phase I detoxification are listed in Table 50.6 .
Curcumin, the compound that gives turmeric its yellow color, is interesting because it inhibits phase I while stimulating phase II. This effect can be very useful in preventing certain types of cancer. Curcumin has been found to inhibit carcinogens, such as benzopyrene (the carcinogen found in charcoal-broiled meat), from inducing cancer in several animal models. It appears that the curcumin exerts its anti-carcinogenic activity by lowering the activation of carcinogens while increasing the detoxification of those that are activated. Curcumin has also been shown to directly inhibit the growth of cancer cells.
As most of the cancer-inducing chemicals in cigarette smoke are only carcinogenic during the period between activation by phase I and final detoxification by phase II, curcumin in the turmeric can help to prevent the cancer-causing effects of tobacco. In one human study, 16 chronic smokers were given 1.5 g/day of turmeric while six non-smokers served as a control group. At the end of the 30 day trial, the smokers receiving the turmeric demonstrated significant reduction in the level of mutagens excreted in the urine. These results are quite significant as the level of urinary mutagens is thought to correlate with the systemic load of carcinogens and the efficacy of detoxification mechanisms. Those exposed to smoke, aromatic hydrocarbons, and other environmental carcinogens will probably benefit from the frequent use of curry or turmeric.
The activity of phase I detoxification enzymes decreases in old age. Aging also decreases blood flow though the liver, further aggravating the problem. Lack of the physical activity necessary for good circulation combined with the poor nutrition commonly seen in the elderly add up to a significant impairment of detoxification capacity, which is typically found in aging individuals. This helps to explain why toxic reactions to drugs are seen so commonly in the elderly.
Phase II detoxification
Phase II detoxification typically involves conjugation in which various enzymes in the liver attach small chemicals to the toxin. This conjugation reaction either neutralizes the toxin or makes the toxin more easily excreted through the urine or bile. Phase II enzymes act on some toxins directly, while others must first be activated by the phase I enzymes. There are essentially six phase II detoxification pathways:
• glutathione conjugation
• amino acid conjugation
Table 50.1 provides examples of toxins neutralized by each of these pathways. Some toxins are neutralized through several pathways.
In order to work, these enzyme systems need nutrients both for their activation and to provide the small molecules they add to the toxins. In addition, they utilize metabolic energy to function and to synthesize some of the small conjugating molecules. Thus, mitochondrial dysfunction, such as found in chronic fatigue syndrome, a magnesium deficiency or physical inactivity, can cause phase II detoxification to slow down, allowing the build-up of toxic intermediates. Table 50.7 lists the key nutrients needed by each of the six phase II detoxification systems. Table 50.8 lists the activators and Table 50.9 the inhibitors of phase II enzymes.
A primary phase II detoxification route is conjugation with glutathione (a tripeptide composed of three amino
TABLE 50-7-- Nutrients needed by phase II detoxification enzymes