Metabolic Pathways of Liver Detoxification Lise Alschuler, N.D., Medical Director, Bastyr Center for Natural Health
The liver is our primary site of detoxification. Hepatic detoxification is comprised of two phases. Phase I refers to cytochrome P450 enzyme detoxification. Phase II refers to conjugation of the detoxified intermediates from Phase I. Detoxification begins within each hepatocyte. The mitochondrial membrane is home to a complex and intricate system of detoxification enzymes. These enzymes, known as the cytochrome P450 (a.k.a. mixed-function oxygenase [MFO] system) occur mainly in the liver and to a lesser extent in the intestines and lungs. The cP450 enzymes are a superfamily of enzymes. Each enzyme is designated by the letters ¡°CYP¡± followed by another Arabic numeral (e.g. CYP2D6). There is significant individual variability since 71 genes code for these enzymes. This variability may explain differences in individual susceptibility to various toxins and individual reactivity to medications and endogenous compounds, such as hormones. The main function of the cP450 system is to convert fat-soluble toxins into water-soluble, polarized compounds, which can then be conjugated and excreted in the bile or urine. These compounds are normally conjugated through one of the following pathways: sulfation, glucuronidation, glutathione conjugation, acetylation, methylation, or other amino acid conjugation.
Upon exposure to toxic substances, the activity of the involved cP450 enzymes increase as a consequence of up-regulation. Also up-regulated are other hepatic detoxification enzymes involved in conjugation, namely sulfur transferase, acetylation and sulfation. Chronic toxic exposure with resultant increase in cP450 system enzymes can cause hepatic and other tissue damage. The detoxified intermediates produced by cP450 enzyme activity can be more reactive than the original toxin. While these intermediates are normally conjugated into non-reactive compounds and excreted, in a state of chronic toxic exposure, the conjugating nutrients (i.e. SOD, Vit. E, Vit. C, carotenes, glutathione peroxidase, glutathione reductase, etc.) may become depleted leading to tissue damage (peroxidation and fibrosis). Conversely, some people have under-active cP450 enzymes, which makes it more difficult to clear hormones and inflammatory compounds (such as histamine). This, in turn, leads to metabolic toxicity and inflammation. Additionally, people with under-active cP450 enzymes are more susceptible to the development of cancer, caffeine intolerance, and environmental sensitivities.
In supporting hepatic detoxification, there are several considerations that must be taken into account. It must be understood that the primary source of toxicity to the liver is the leakage of gut-derived toxic compounds into the blood. The majority of these are endotoxins. Given this influx of toxic compounds from the gut, the first step in a detoxification support program must be to assess and restore optimal intestinal permeability. Many individuals suffer from hyperpermeable intestines as a consequence of dietary allergens, intestinal exposure to inflammatory compounds, impaired gut associated lymphoid tissue function, and/or intestinal exposure to certain medications (such as certain chemotherapeutic agents). In these individuals, intestinal permeability testing may be considered (lactulose/mannitol loading test is considered the most reliable test). If increased intestinal permeability exists, a treatment program for restoration of the intestinal barrier is the crucial first step in a detoxification program. This treatment may involve dietary manipulation, L-glutamine, demulcent herbs (Ulmus fulva, Althea officinalis, etc.), etc.
Once the intestinal reparative therapy is well underway, the next step in supporting hepatic detoxification is to directly support Phase I and Phase II detoxification. Some clinicians find that measuring aspects of Phase I and Phase II detoxification is a helpful way to provide specific detoxification support. Liver detoxification profiles are available from a number of independent laboratories. These tests usually include a caffeine clearance test to measure Phase I and several conjugation tests to determine the activity of Phase II. Based upon these test results or one's clinical assessment, a comprehensive program of hepatic detoxification support should be initiated.
If Phase I is determined to be overactive, several interventions may be helpful. Removal of environmental and lifestyle factors which up-regulate cP450 enzyme activity is the first step. These include: chronic toxic exposure, alcohol, smoking (nicotine), polycyclic aromatic hydrocarbons (formed during charcoal broiling and found in cigarette smoke), acetominophen (Tylenol), Phenobarbital, indoles (found in Cruciferous vegetables), iron deficiency, and a high protein diet. On the other hand, if cP450 is determined to be under-active, it is necessary to address factors that cause this down-regulation. Factors which down-regulate cP450 include: under-nutrition, fasting, protein deficiency, phosphatidylcholine deficiency (PUFA deficiency), benzodiazepines (Halcion, Librium, Valium, etc.), Antihistamines, Cimetidine (Tagamet), Ketoconazole, Sulfaphenazole, naringenin from grapefruit juice, vitamin C and A deficiencies, and bacterial endotoxins.
Once Phase I activity is proportional to the toxic load, additional support may be required for Phase II conjugation activities. Based upon liver detoxification test results, or clinical judgement, specific or generic Phase II support is often indicated. One type of phase II conjugation is adding an acetyl group to a cP450-produced metabolite. There is great individual variability of acetylation rates. Acetylation detoxifies sulfonamides and mescaline. Acetylation is inhibited by deficiencies of vitamin B2, B5, or Vit. C. There are no known inducers.
Glutathione is an important conjugating molecule. Glutathione is a tripeptide composed of glutamic acid, cysteine and glycine. The conjugation of glutathione with intermediary biotransformed xenobiotics from Phase I results in the excretion of mercapturic acids. Glutathione has two major functions in the body: conjugation to form mercapturic acid and quenching oxygen free radicals. Therefore, if the glutathione is used up in its conjugating role, there will be less avai |