Detoxification -- A Clinical Perspective

Detoxification -- A Clinical Perspective

The tenets of naturopathic medicine include prevention of disease and stimulation of the healing power of natural processes. These time-tested principles are a rallying call for many integrative practitioners who are seeking more harmonious means of treating patients.

There are multiple syndromes, pathologies and diagnoses with which a person may be labeled. The diagnosis represents a tremendous psychological influence with the patient by providing a scientific image of what they are going to become ("a person with ______"), how their body is being damaged, and what course and limitations may be expected with the disease. This can lead to the patient identifying with a pathological persona unwittingly presented by the physician or through the media and interactions with family and friends.

Obviously, this is not the intent of the conscious physician/healer. We can, however, be seduced by our capacity for gnosis, and may lose sight of the need to present a positive possibility for the patient, regardless of what the medical diagnosis and prognosis indicate may be expected.

DETOXIFICATION REPRESENTS POTENTIAL

The process of detoxification is as powerful as news of a devastating diagnosis. It holds out to the patient the possibility of changing the current process their body (and mind) is immersed in. It allows them to paint their own picture of just what exactly they need "detoxified," whether that be an organ, organ system, attitude, relationships with other people or society at large. Detoxification is a term sufficiently general to afford unlimited potential and one that does not prevent physicians from pursuing specific -- even aggressive -- treatments at the same time.

This peculiarly naturopathic model arises from roots in the curative traditions of Kneipp, Kellogg and other hydrotherapy or "nature-cure" predecessors. Detoxification acknowledges and stimulates both general and specific healing capacities. Interventions based on this principle may be as simple as ensuring the repleteness of the diet and low-level supplementation with antioxidant nutrients. The other end of the spectrum is represented by the extensive systemic xenobiotic clearing regimens attempted by specialized clinics. Many practitioners find a middle ground and incorporate strategies such as those below that have far-reaching ramifications central to the healing process.

TOXINS: TODAY'S REALITY

Public acknowledgment regarding the extent of environmental exposure to xenobiotics is at an all-time high. The concern is real and tangible. The EPA data for toxic chemical release by industry show the following statistics for the United States alone (this does not include agricultural or household applications):( 1) 1994 On-site land (up from 2.5 million 1992)

4 million pounds 1994 Releases into surface water

25 million pounds 1994 Releases into the air

42 million pounds 1994 On-site deepwell injection

40 million pounds Total reported toxic chemical release (1994)

111 million pounds Total estimated toxic chemical release (1994)

2 billion, 200 million pounds

It is clear that our disposition of chemicals results in our eventual exposure to toxic compounds via water, air and foodstuffs. The crucial determinations as to the effects of these exposures are becoming evident. Tissues accumulate specific toxic agents, with reproductive, liver and adipose tissue the most prevalent storage sites. Human seminal plasma contains compounds such as pentachlorophenol, hexachlorobenzene, DDT metabolites and PCBs. Adipose tissue also contains PCBs, DDT metabolites and chlordane.( 2) There are indications that tissue deposition is an increasing problem worldwide, particularly among populations with high exposure. In one study of hexachlorobenzene content in adipose tissue, it was shown that the median levels actually increased by 50% over levels determined five years previously. Pesticide-exposed wine growers had twice the median levels.( 3)

The functional changes resulting from these xenobiotic accumulations can be profound. There are particularly insidious findings that indicate the traditional view of toxicology may need to be modified when dealing with the subtler functions of hormones and receptor physiology. In both human and animal tissue preparations, small compounds which were previously considered inert were shown to bind with steroid receptors and affect hormonal status. The compounds naphthalene, anthracene and biphenyl demonstrated stronger affinities for glucocorticoid and androgen receptors after being acted upon by hepatic conjugation reactions.( 4) Another concern is recent observation that combinations of xenobiotics may have effects on hormonal status far beyond their sums of activity.( 5) In an experimental model utilizing human estrogen-receptor (hER), it was shown that the combination of two weak environmental estrogens (dieldrin and toxaphene) had 1,000 times the effect of either one alone in competitive hER binding studies with beta-estradiol.( 6)

TOXIC ELEMENTS

Testing for the presence of toxic elements such as Hg, As, Pb, Cd, U and Al can be an integral part of the overall treatment protocol. These toxic elements are largely undetected by standard labwork, yet toxic symptoms may occur due to ongoing chronic exposure or the presence of other xenobiotics.( 7) In addition to their subtle but cumulative metabolic toxicity, these heavy metals tend to impair the phase I pathways such that xenobiotics may have intensified negative effects.( 8) Antimony exposure depletes hepatic glutathione in rat models, raising the possibility that similar mechanisms may be at work in humans. If this is the case, liver detoxification capacity would be impaired (i.e. low glutathione S-transferase [GSH] conjugation), making the effect of other toxic compounds become more problematic.( 9) Elevated uranium levels, while not necessarily reflecting exposure to the radioactive isotope, often manifest as fatigue which is refractory to the usual regimens.( 10)

Elemental analysis of hair or provocative urine testing can help determine if the body burden of these elements is excessive.( 11) If positive findings occur, these provide a clear therapeutic direction quite different than if these elements are not sought in initial testing. The identification and removal of toxic elements, such as those above, can make a profound difference in patients with fatigue and cognitive disorders. The excretion of the elements can be monitored via the urine. Thus, elemental analysis answers a pivotal question in determining whether to perform laboratory studies; the results from such studies can (and should) modify the treatment approach.

Some commonly utilized nutrients are effective in the diminution of toxic element burden -- vitamin C is perhaps first among them. Others may create complicated interactions which can cause difficulty for patients. For example, it is not recommended to administer significant amounts of L-cysteine if there are elevated levels of mercury in the body as there is avid binding but not necessarily increased excretion of the Hg-cysteine complex. If the presence of toxic elements is detected with elemental analysis, a better course of treatment is reduced glutathione.( 12) As there is evidence that some xenobiotic metabolism via glutathione can create damaging metabolites, I recommend a hearty array of other antioxidants be used concomitantly with reduced glutathione or forms of cysteine, taurine, ascorbate, lipoic acid, mixed tocopherols, carotenoids and selenium.( 13)

Clinical Presentations

There are a number of common warning signs indicating that toxicity may be involved in a particular patient. These include a history of increasing sensitivity to exogenous exposures (foods, allergens, chemicals, stressors), abundant use of medications or chemicals in the home or work environment, and fatigue. A list of common symptoms experienced by the person with an appreciable degree of toxicity include: odor and medication sensitivity, musculoskeletal symptoms (similar to fibromyalgia), cognitive dysfunction, unilateral paresthesia, autonomic dysfunction and recurrent patterns of edema. Worsening of symptoms after anesthesia or pregnancy and paradoxical responses to medications or supplements may also occur.( 14)

Two specific conditions, encephalopathy and pancreatitis, provide examples of how xenobiotics can influence clinical pictures. Exposure to various solvents is correlated with development of chronic toxic encephalopathy, which may present as diverse neuropsychiatric disorders. A genetic defect in one of the glutathione-transferase enzymes (and therefore GSH-conjugation deficiencies) results in lowered detoxifying capacity and greater likelihood of encephalopathy.( 15) Idiopathic pancreatitis can be associated with upregulation of the cytochrome p450 enzymes in many patients. Patient histories often include exposures to diesel fumes, paint solvents and trichloroethylene. These xenobiotic exposures also seem to accentuate the susceptibility to ethanol-related pancreatitis.( 16)

Hepatic and Upper Gut Toxicity

Another clinical issue relating to excretion of xenobiotics and protection from the irritative metabolites resulting from exposure, is the evolution of "toxic bile." The qualities of bile vary according to a number of factors including hepatic biliary secretory capacity, changes in transcellular systems of transport carriers, proteins, and conjugating systems and mechanical or pathological obstruction of the bile ducts. Modifications to these processes may result in conditions which impair the elimination of xenobiotics and increase their toxicity in vivo.( 17) There are indications that two amino acids, glycine and taurine, play a part in reducing some of the cellular toxicity of bile acids. They provide a useful adjunct to therapy in cases of cholestasis or toxin exposure.( 18) The use of supplemental taurine in cases of inflammation of the hepatobiliary tract and in the upper gut is strongly indicated as this amino acid quenches the reactive species elaborated during leukocyte respiratory burst activity.( 19) Use of activated charcoal is good therapeutic practice in cases of known exposure as well. This benign substance binds with xenobiotic compounds, preventing absorption and rendering them less reactive as they travel through the gut.( 20)

Use of silymarin in the area of hepatoprotection is proven. However, there are other mechanisms of action which may prove of particular help. In addition to its strong antioxidant activities and ability to increase intrahepatic GSH levels, silymarin shows ability to modify gene expression via DNA polymerase and to increase the stability of cell membranes in the face of xenobiotic exposure.( 21) It has also been shown clinically to normalize hepatic inflammatory patterns after exposure to xylene and or toluene.( 22)

L-carnitine can influence the excretion of xenobiotics. This compound, by its actions of improving fatty acid utilization by the mitochondria, plays a part in fatty acid mobilization and may enhance elimination of lipophilic chemicals. In supplemental administration, one study noted that this natural agent ensures elimination of xenobiotic substances.( 23)

Phase I: Metabolism and Modulation

Functional liver testing/detoxification assessments are often used to evaluate impairments or imbalance of phase I and phase II detoxification capacities (for a discussion of this topic, see the Quarterly Review of Natural Medicine, Spring 1996 article by Dr. Lukaczer).

The cytochrome p450 system of hepatic enzymes is a significant player in the capacity to efficiently metabolize toxins. This system (phase I) is largely responsible for oxidation or hydroxylation of chemical compounds preparatory for conjugation reactions (phase II) which enhance hydrophilic properties and excretion. This system consists of families of many enzymes. Six of these are important in humans:

cyp1A2: These enzymes are active in the biotransformation of polycyclic hydrocarbons, heterocyclic amines, aflatoxin and many xenobiotics. Caffeine, Tylenol and arachadonic acid are metabolized by this system. This enzyme system is induced in humans by cigarette smoke and other xenobiotics.( 24)

cyp2A6: This system acts on plant-coumarin-type compounds and is inhibited by the antifungal agents ketaconazole, miconazole and clotrimazole.

cyp2C: This system (four subfamilies in humans) acts on warfarin, the antiprotozoal pentamidine, verapamil, phenytoin, benzopyrenes (from cigarette smoke, fossil fuel combustion) and is the major cyp metabolizing arachadonic acid.

cyp2D6: These enzymes work on many drugs such as codeine, amitriptyline, methadone and endogenous steroids; however, their prevalence in the body is fairly low as a percent of the total cytochromes. There is some evidence that low levels of this enzyme are related to increased risk for Parkinson disease via a toxin-exposure mechanism. High levels may be correlated to certain cancers.

cyp2E1: This system is responsive to individual dietary/lifestyle factors and may be partially regulated by insulin levels. It metabolizes ethyl alcohol, fatty acids such as linolenic acid, and small molecular weight lipophilic molecules (e.g. hexane, pentane) which include many xenobiotics. Common medications and food constituents such as acetaminophen, salicylates and caffeine are processed by this system.

cyp3A4: This system is responsible for beta-hydroxylation of steroids. Lovastatin, phenobarbital, phenytoin, acetaminophen, erythromycin and prednisone are examples of drugs transformed by this system.( 25, 26)

Natural Product CYP Modifiers

The p450 system is an example of how genetic polymorphisms can translate into increased risk for certain cancers and susceptibility to toxins. Such phenomena in humans include cyp 1A2, 2C, 2D6, and 2E1 polymorphisms, with xenobiotic synergism and induction leading to increased toxicity or cancer risk.( 27) With this in mind, listed below are some of the natural product and dietary compounds shown to influence the activity of some of the above enzyme systems. Many of these studies were done with human cell models, some with animal models, and some with patients. While these studies are by no means definitive, they describe intriguing relationships between dietary plant constituents and variability at this level of cellular physiology.

Flavonoids: Quercetin, kaempferol and naringenin occur in many fruits and vegetables including grapefruit juice, red onions, and medicinal herbs such as Calendula officinalis, Tilia cordata, Sambucus nigra, Betulae folium and Solidago virgaurea.( 28) These flavonoids have been shown to inhibit activity of cyp 1A2 and 3A4 while the flavonoids tangeretin and nobeletin (from orange juice) are shown to induce cyp 3A4.( 29)

Monoterpenoids: The compound D-limonene derived from the oil in lemon has a number of interesting effects on the detox systems. In animal models, it increases levels of cyp 2C and improves resistance to glutathione depletion by chronic acetaminophen administration.( 30, 31) It also inhibits the activity of cyp 2E1 in animal models.

Curcumin: This compound has profound effects on a number of systems. In animal hepatocyte models, it strongly inhibits the activity of cyp 1A2 and of the glutathione S-transferase enzyme.( 32, 33)

Coumarin-containing plants which are metabolized by the 2A6 family include: Fraxinus americana, Galium verum, Melilotus officinalis, Ammi visnaga, and Bupleurum chinense.( 34, 35) These plants may be useful in competitively occupying the enzyme system thereby effectively increasing the availability of other medications similarly metabolized.

Forskolin: As many xenobiotics are stored in the adipose tissue, enhancement of lipolysis during a detoxification regimen can be of significant benefit. This natural product, derived from Coleus forskohlii, may be useful in increasing the cAMP levels which can indirectly assist (via adenylcyclase) with lipolysis.( 36, 37)

Indole-3-carbinols: These compounds are found in the brassica family of vegetables (cabbage, brussel sprouts, broccoli). They inhibit the activity of the 1A1 and 1A2 isoforms of cytochrome in humans.( 38) They also have the capacity to enhance the phase II glutathione pathway, thereby providing a means to clear xenobiotics more efficiently.( 39)

Cytochrome Modulation/Applications

The phase I pathways (cyp 450s) may respond to induction or inhibition via dietary manipulations and or specific natural product supplementation. There are situations where inhibition may be a useful strategy. A recent series of tests performed on autistic children showed a preponderance of these patients had high levels of detoxification end products yet had little reserves for detoxification under challenge testing. The majority of these children were classified as "pathologic detoxifiers" with high levels of phase I activity and relatively low levels of the phase II pathways.( 40) This is one situation where temporary down-regulation of the phase I (cyp 450) enzymes may be of benefit. It should be noted that some of these patients had a significant xenobiotic load likely to have caused the high cyp 450 activities.

Another example of potential benefit with cyp inhibition is treatment of chronic inflammation and autoimmunity. Studies indicate that cyp 1A2 and 2C are significantly involved in the metabolism of arachadonic acid in human liver cells.( 41) Interestingly, cyp inhibitors have also been shown to decrease IL-2 synthesis resulting in less cytokine-induced T-cell proliferation and, therefore, a measure of immunosuppression.( 42) Consequently, the use of natural cyp inhibitors such as curcumin and quercetin appear to address inflammation at its cellular origin by modifying arachadonic acid metabolism and by quieting excessive immuno-reactivity.

Insulin-dependent diabetes tends to up-regulate cyp 1A2 and this correlates with elevated 2E1 levels as well.( 43) If phase II pathways are unable to accommodate this higher output of metabolites, increased oxidative damage is likely to occur. This helps explain the strong need for antioxidant support in this condition as well as the potential therapeutic use of lemons, brassica-family vegetables, quercetin and curcumin.

This strategy of p450 inhibition should be performed with attention to removal of as many offending substances as possible. If the exposure to xenobiotics persists during the period of inhibition, there exists the potential for greater deposition of xenobiotic compounds in the adipose and other tissues. Drugs, toxin exposures at work and home, cigarette smoke, caffeine, alcohol and fried or charbroiled meats can modify activity of the p450 enzymes or phase II systems when ingested, and are best avoided.

Phase II: Metabolism and Modulation

After modification by the activities of the cyp 450 system, transformed products are then typically metabolized by the (phase II) conjugation pathways to allow efficient excretion of water-soluble products via the urine or bile. These systems -- acetylation, glucuronidation, sulfation, methylation and glutathione conjugation -- are quite variable in their capacities, are frequently overlapping in substrate affinities and are under a significant degree of control via inducers/inhibitors.( 44) The activities of these pathways may be measured via challenge testing utilizing aspirin, acetaminophen and caffeine. These results enable the physician to devise specific treatments.

The conjugation enzymes exist primarily in the liver, but are also found in other tissues, particularly the intestinal villi. Additional evidence for the importance of mucosal integrity in detoxification mechanisms is implied by the presence of p450 enzymes present on the villi as well.( 45, 46) With this last point in mind, it behooves the practitioner to focus on the intestinal environment as well. Identification and treatment of constipation, dysbiosis and parasitic or Candida albicans overgrowth is integral to success since the gut microenvironment can be a significant contributor to systemic toxicity.( 47)

Some of the required nutrient substrates necessary for efficient sulfation reactions include vitamin A, adequate protein in the diet, and adequate sources of dietary sulfur (from the amino acids methionine, cysteine and foods such as garlic and onions).( 48, 49) Glucuronidation reactions require magnesium and may be inhibited by smoking, fasting and possibly high fructose intake. As this is a membranebound enzyme system, the integrity of the lipid bilayer is important for efficient glucuronidation.( 50) Glutathione reactions are some of the most crucial in the deactivation of xenobiotics and participate in arachadonic acid metabolism too. They require adequate vitamins B6 and B12, Mg, and folate for the conversion of methionine and cysteine to glutathione. GSH transferases may be inhibited by a number of dietary constituents, including alcohol and plant phenols, while they are induced by brassica-family compounds.( 51) Amino acid conjugation may be enhanced by administration of the amino acid (glycine or taurine) itself. Testing via the challenge procedure helps identify individual deficiencies in the detoxification pathways and permits customized treatment.

Ahh...At Last, the Sauna

A technique of historical use and of current resurgence which assists with the detoxification process is the sauna or Finnish bath. This system of exposure to high temperatures for extended periods has generated many studies concerning its merit and potential dangers. Investigations with this procedure have been performed showing its safety in cardiac patients. Peripheral hemodynamics are typically improved, therefore the expected increase in cardiac stress is mininized.( 52) Other cardiac parameters such as ejection fraction and stroke volume improved as well.( 53) A study performed with patients after coronary bypass or aneurysm repair showed very good results in improved cardiac measurements.( 54)

In regard to our topic here, sauna therapy assists with the excretion of xenobiotics, including PCBs, cadmium, lead and industrial chemicals used in the rubber industry.( 55, 56, 57) As appreciable amounts of essential minerals are also lost in the sweat among even acclimatized people, replacing these via diet or supplements is an important treatment component.( 58)

A key influence of the sauna is stimulation of lipolysis and improved excretory potential of stored xenobiotics. There are dear indications that sauna therapy is quite efficient in this regard. Lipolysis is stimulated by beta 1 and beta 2 adrenergic activation. There are differences in adipose sensitivity to this stimulation, governed by location of the fat stores, cAMP and insulin secretion among other factors.( 59, 60) Norepinephrine strongly stimulates lipolysis. Accentuated release and maintenance of elevated levels of this catecholamine occur with sauna therapy.( 61, 62) In addition, this beta-adrenergic lipolysis can be further increased by the presence of growth hormone.( 63) Studies show that growth hormone levels are significantly increased with sauna therapy.( 64, 65)

Thus, in this age-old tradition, we find evidence of a cumulative hormonal effect which enhances lipolysis, freeing stored lipophilic toxins, while the physical conditions of high heat enhance peripheral circulation and excretion of xenobiotics and toxic elements via the sweat.

Conclusion

Detoxification frequently has lasting effects far beyond the expectation of the practitioner. Key aspects of individual health may be addressed, from the biochemical to the transpersonal. When combined with sauna therapy, it provides the patient with a fruitful time for introspection and slowing down, which for many is a crucial, healing respite from the demands of their lives.

The process of working together to identify areas of toxicity on many different levels brings about a mindset of unique possibility unlikely to occur in a more typical office setting. Massage therapy may be integrated into a series of treatments with great facility and positive response. In short, the person may be empowered and assisted along the way to self-determination, to the deep realization of who they really are. This represents the most profound level of health and healing.
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Article copyright Natural Product Research Consultants, Inc.

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By John H. Furlong

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