The following is condensed from The Moss Nutrition Report by Jeffrey Moss, D.D.S., C.N.S., C.C.N. in an excellent five part series on toxicity and detoxification. To subscribe for text and references call (800) 851-5444 or visit www.mossnutrition.com
If pollution is everywhere, where do you hide when there is no place left to hide? Zimmerman, H.J. states in his 1999 text on liver toxicity, Hepatology, Second Edition: “Viewed broadly, all nonpolar foreign compounds are potentially toxic. Aqueous insolubility of a compound precludes effective excretion of it in the urine, because nonpolar compounds are reabsorbed by the renal tubule. The resulting accumulation in the body could become an intolerable chemical burden if these nonpolar compounds were not converted to polar products." If the world is and always has been toxic, why is it that so many people, past and present, have appeared to live symptom-free, happy lives without “glass bubbles?” We need to not only understand the two-step process necessary for detoxification in the liver, but also in many organs and systems beyond the liver that we seldom hear about as detoxifiers.
Phase I-II reactions: Toxins and hormones both go through virtually the same detoxification pathways. In typical Phase I reaction, a cytochrome P450 enzyme uses oxygen and, as a cofactor, NADH, to add a reactive group, such as a hydroxyl radical. As a consequence of this step in detoxification, reactive molecules, which may be more toxic than the parent molecule, are produced. If these reactive molecules are not further metabolized by Phase II and conjugated by glucuronidation or sulfation to become polar molecules for safe excretion, they may cause damage to proteins, RNA, and DNA within the cell. Glucuronidation is the more common pathway of metabolism for many endogenous compounds including steroid hormones, catecholamines, bilirubin and thyroxine. Sulfation is the primary route of metabolism for catecholamine neurotransmitters, steroid hormones, thyroxine, bile acids, phenolic drugs, and other foreign compounds. The total pool of sulfate is usually limited and can be readily be exhausted. Therefore, it could be hypothesized that high levels of toxins could impair sulfation of endogenous compounds and visa versa. Consider Methionine-200 or Garlic Plus as good sulfur sources. Vitamins B2, B3, B6, B12, folic acid and glutathione and branched-chain amino acids are involved with phase I metabolism. Phase II requires methionine, cysteine, glycine, taurine, glutamine, ornithine, arginine. Garlic oil, rosemary, soy, cabbage, and brussels sprouts all contain compounds that can induce several Phase II enzyme activities. In general, increase in Phase II activity supports better detoxification in an individual and helps to promote and maintain a healthy balance between Phase I and Phase II activities. Consider MCS at 1-2 a day and GSH-Plus at 1-3 a day.
CYP3A4 may fairly be regarded as the most important human CYP (a cytochrome P450 enzyme) of Phase I. It has been estimated that CYP3A4 constitutes up to 50% of the total CYP in human liver and metabolizes approximately half of all therapeutic agents. CYP3A4 are also found in significant amounts outside of the liver. Extrahepatic detoxification is just as important to consider in your patients as hepatic detoxification. The most striking feature of the nasal epithelium is that CYP450 catalytic activity is higher than most any other tissue, including the liver. Nasal decongestants, essences, anesthetics, alcohols, nicotine, and cocaine have been shown to be metabolized in vitro by CYP450 enzymes from the nasal epithelium. While only expressed in trace amounts in the kidney, the relative levels of CYP3A4 (in % of hepatic level) were 50% in duodenum, 30% in the jejunum, 15% in ileum, 4.3% in stomach, 2.5% in esophagus, and 1.5 in colon. In healthy subjects, CYP3A4 accounts for approximately 70% of total P450 present in enterocytes lining the gut. Significant CYP450 activity can be also found in the skin, placenta, and breast (both normal tissue and tumors). Concerning the breast, it should be noted that, similar to the pharynx and nasal tissue, the fact that it contains CYP450 enzymes means that breast-specific carcinogens do not have to rely on hepatic biotransformation to cause neoplastic change. The machinery for possible in situ bioactivation of xenobiotics and modification of therapeutic drugs is thus also present in human breast tissue.
Both CYP450 and glucuronidation enzymes are found in the lung and kidney. Concerning lung detox enzymes, phase I activity is of minor significance while phase II conjugation pathways are comparable to those in the liver. The lungs play a significant role in the metabolic elimination or activation of drugs and xenobiotics. When drugs are injected intravenously, intramuscularly, or subcutaneously, or after skin absorption, the drug initially enters the pulmonary circulation after which the lung becomes the first organ of first pass metabolism for the drug. The clinical significance of lung detoxification enzymes is its position in the circulation. Because the lung provides a second pass metabolism for xenobiotics and their metabolites exiting the liver, it is also susceptible to the cytotoxicity or carcinogenicity of hepatic activated metabolites. Antihistamines, beta blockers, opioids, and tricyclic antidepressants are among the basic amines known to accumulate in the lungs as a result of their binding to surfactant phospholipids in lung tissue. In patients suffering from ‘flu, the increased interferon production results in the transient reduction of the activity of cytochrome P450. Consider Pneuma-Zyme and BioProtect each at 3 a day; Renal Plus for kidney.
The first contact the body makes with the majority of xenobiotics is the gastrointestinal tract. Over the course of a lifetime, the gastrointestinal tract processes more than 25 tons of food, which represents the largest load of antigens and xenobiotics confronting the human body. It provides a physical barrier and contains the large amounts of cytochrome P450 enzymes. The intestine has a dual personality. Gut microflora can produce compounds that either induce or inhibit detoxification activities. Pathogenic bacteria can produce toxins that can enter circulation and increase toxic load. In a process called enterohepatic recirculation (ER), gut microflora also have the ability to remove some conjugation moieties, such as glucuronyl side chains, converting the xenobiotic to its original form, and allowing it to reenter circulation, also leading to an increased toxic load. And there exist several physiologic pathways, such as hormone metabolism, where ER is absolutely essential for maintaining optimal levels of certain reproductive hormones and nutrients; CYP3A4 is involved in the metabolism of endogenous steroids, including testosterone, progesterone, cortisol, androstenedione, and estradiol. Patients with celiac disease have low CYP3A activity. A gluten-free diet fosters microflora that raises CTP3A. To maintain healthy gut/microflora, as needed, Hydro-Zyme, Beta Plus, Livotrit Plus, Colon Plus, ADP, Bromelain Plus CLA, Lactozyme, Gastra-Zyme, etc.
Measurement of CYP3A4: As most of you know, the caffeine challenge test has been used to ascertain cytochrome P450 activity. Unfortunately, it’s value primarily lies with CYP1A2 determination. Fortunately, there exists a simple urinary test that has been recognized for years as an excellent way to determine CYP3A4 activity. It involves the ratio of the cortisol metabolite 6-b-hydroxycortisol to cortisol. It is the test to request.
If a patient is under excessive psychological or physical stress, both of which increase use of both glucose and glycogen for energy production, glucuronidation can be impaired. We know that high cortisol levels from stress lower insulin function (Syndrome X) in order to maintain high serum sugar levels for fight or flight activity. Cortisol increases phase I (CYP3A4) activity to thus increase free radical levels but it concurrently lowers phase II activity since the enzymes needed for glucuronidation that are being used for glucogenesis. Anyone on a high carbohydrate diet while stressed has quadruple insult to detoxification. Stress can transform a substance that, under normal conditions is fairly benign, into a substance that might be quite harmful. Stress accentuates the toxicity of substances that, on their own, are already detrimental to health. Before major detoxification procedures begin, all patients need to go through 30-60 days of basic dietary correction, stress management, and supplementation to improve insulin metabolism and digestive function. Note: A critical diagnostic test is salivary cortisol. For dysinsulinism consider using BioGlycozyme or Glucobalance; for elevated cortisol, ADHS; for depressed cortisol, Cytozyme AD; to raise CYP3A4 specifically, St John's Wort; and to reestablish phase II, MCS.
The Adrenal Gland in Toxicology: Optimal adrenal function is every bit as essential to expedient elimination of xenobiotics as is the liver and kidneys. A wide variety of xenobiotics are metabolized by adrenocortical enzymes. In the adrenal cortex, in addition to their central role to steroidogenesis, cytochrome P450 enzymes are important mediators of toxicological effects. If the adrenals are not operating properly, the effects of sometimes fairly benign chemicals can be greatly enhanced. Adrenocortical cells contain high concentrations of biological antioxidants including superoxide dismutase (SOD), catalase, a-tocopherol, glutathione and, in particular, ascorbic acid. It has been suggested that these high levels of antioxidants serve to protect cytochrome P450 enzymes from toxic effects of oxygen radicals generated during steroid biosynthesis. The amount of lipid peroxidation resulting from a non-specific stimulus is far greater in adrenocortical than in hepatic mitochondrial or microsomal preparations.
The immune system, the brain and CYP450 activity: Several cytokines, in particular the interferons, influence the activity of cytochromes P450. Of major significance to the disposition of drugs is that the loss of cytochrome P450 in the brain during CNS inflammation is accompanied by a concomitant loss of cytochrome P450 in the liver. This suggests that the hepatic clearance of some drugs will be compromised during periods of CNS inflammatory disease. TNF and other cytokines might play a role in the development of brain inflammation caused by infection, Alzheimer disease, multiple sclerosis or physical injury. With patients experiencing elevated levels of either exogenous or endogenous interferon, you may find it difficult to detoxify such patients. Efforts to detoxify patients being treated with interferon (e.g., hepatitis C patients) or those patients who often suffer from colds and influenza may be significantly impaired. Stress physiology mediated by excessive amounts of cortisol may be sabotaging your efforts. Consider the use of herbs that have anti-inflammatory/antioxidant effects on the brain such as Gingko Biloba. An antioxidant nutrient that will also cross the blood-brain barrier is Lipoic Acid. Supplements that reduce acute inflammation (i.e., chymotrypsin and trypsin containing products) can be very helpful. Consider Intenzyme Forte at 5 tablets, 4 times a day on an empty stomach. Natural detoxifying is gentle when we pay attention.