해독의 생화학
DETOXIFICATION OVERVIEW
Detoxification is the conversion of non‐polar (lipophilic) toxins into polar (hydrophilic), non‐toxic metabolites, for their ready elimination by the excretory organs (kidneys, liver, lungs,
and skin)
The detoxification process occurs in two classical steps –
Phase I and Phase II
The products generated from Phase I reactions are often reactive intermediate metabolites and/or reactive oxygen species, which may cause tissue damage.
The reactions in Phase II generally involve conversion of the
intermediate metabolites of Phase I into the final products that are eliminated
it is essential that they function in balance with one another in order to minimize
the presence of intermediate metabolites and carry through an effective detoxification.
seventy‐five percent of detoxification activity occurs in the liver
the remainder takes place in the intestinal mucosa wall.
Although we usually think of the liver as “the” detoxification site, it makes sense that the intestine also plays an important role in detoxification, since the gastrointestinal lining provides the initial physical barrier to the largest load of xenobiotics, including orally ingested drugs.
The GI tract has indeed developed a complex physical and biochemical system to manage this load, as evidenced by the high concentration of detoxification enzymes present in the tip of the villi,7,8 and by the “antiporter activity”
The GI tract also influences detoxification by hosting gut microflora capable of producing
compounds that may either induce or inhibit detoxification.
THE DETOXIFICATION PROCESS in the liver
PHASE I DETOXIFICATION SYSTEM
Initially, toxins are typically non‐reactive compounds(e.g., petrochemical hydrocarbons, drugs,
and steroid hormones). This means that they do not contain a reactive site that can bond to
the water‐soluble moieties of the Phase II reactions. In Phase I, these toxins are subjected to
oxidation, reduction, or hydrolysis reactions – also referred to as functionalization – which
transform them into substances ready for the Phase II process. Infrequently, the end product
of Phase I is directly eliminated.12
Phase I reactions are catalyzed by a multitude of enzyme activities; the most significant one
is the cytochrome P450 (CYP450) supergene family of isoenzymes (mixed function oxidases),
which have very broad substrate specificity.13 The CYP450 enzymes use oxygen and the reduced
form of nicotinamide adenosine dinucleotide (NADH) as cofactor, to add a reactive group
(i.e., hydroxyl radical) to the substrates. The result of this reaction is the generation of a
reactive molecule, which is often more toxic than the parent compound. Unless this intermediate
metabolite is further metabolized by a well‐functioning Phase II system, it may react with and
cause damage to proteins, RNA, and DNA within the cell. Furthermore, Phase I reactions also
generate damaging free radicals.
Over 10 families of CYP450 enzymes have been identified in humans. Each of these families
may contain several subfamilies of enzymes, grouped according to the degree of amino acid
similarity between the enzyme proteins. The individual CYP450 isoenzymes are thus categorized
by family and subfamily. The human liver contains CYP450 activities such as CYP3A4/5,
CYP1A1, CYP1A2, CYP2D6, and CYP2C; their relative amounts reflect their importance in
the metabolism of drugs and exogenous toxins, as well as endogenous molecules such as
steroids.14,
PHASE II DETOXIFICATION SYSTEM
In this phase, the biotransformed molecules generated in Phase I are conjugated by the addition
of a water‐soluble group to the reactive site; this increases their solubility and thus facilitates
excretion in the urine or bile.13 Occasionally, in parent toxins with particular chemical
configurations, Phase II proceeds directly without intermediary Phase I. The enzyme‐mediated
conjugation reactions of Phase II – glucuronidation, amino acid conjugation, sulfation,
acetylation, glutathione conjugation, and methylation – require the presence of energy in the
form of adenosine triphosphate (ATP), and cofactors obtained through dietary sources.
The main types of enzymes catalyzing Phase II reactions are: glucuronyl transferases, glutathione transferases, sulfotransferases, N‐acetyl transferases, N‐ and O‐ methyl transferases, amino acid transferases, and epoxide hydrolase.
해독의 임상 적용
INTRODUCTION
The human detoxification system is driven by a complex network of enzymatic reactions and
is regulated by a large number of mechanisms. Since these mechanisms are affected or
modulated by numerous external and internal factors, it is now recognized that each individual
has a particular “detoxification profile” defined by his/her own specific environmental and
genetic conditions. The variability in individual detoxification capacity could explain why,
in a large population exposed to the same levels of carcinogens, some persons develop cancer
while others do not.1
The steady developments in the field of toxicology and detoxification continue to provide the
clinician additional tools for the identification of factors that affect the individual’s detoxification pattern. They also continue to expand the healthcare provider’s ability to apply programs that improve the outcome of diseases affected by dysfunctional detoxification.2,3
The extensive research in the past few years on the individual’s ability to detoxify multiple
xenobiotics has significantly increased our clinical understanding of detoxification.6,7 For
example, it has provided information about the damaging effect(s) of alcohol and smoking,
which result in an increase of highly reactive compounds and free radical formation. Most
significantly, it has pointed out the key role that nutrition has in the multiple mechanisms
involved in detoxification, both as a source of the essential cofactors and conjugation moieties,
and providing support for the production of the energy required by those mechanisms.
해독 기능 이상의 임상 양상
임상 증상:
Several warning signs may be indicative of toxicity in an individual, including:
• A history of increasing sensitivity to exogenous exposures, odors, or medications
• Abundant use of medications or potentially toxic chemicals in the individual’s
environment
• Musculoskeletal symptoms (similar to fibromyalgia)
• Cognitive dysfunction
• Unilateral paresthesia
• Autonomic dysfunction
• Recurrent patterns of edema
• Worsening of symptoms after anesthesia or pregnancy
• Unusual responses to medications or supplements.
해독 기능 이상과 관련된 임상 질환
CHRONIC FATIGUE and RELATED SYNDROMES
Researchers have suggested the existence of a relationship between the symptoms
presented by Chronic Fatigue Syndrome (CFS) patients and impaired detoxification
resulting from toxic exposure.8 In two separate studies, reducing toxic insults through
diet and lifestyle modification, along with nutritional support of detoxification pathways,
achieved significant improvement of symptoms in patients affected by CFS.
9,10
MULTIPLE CHEMICAL SENSITIVITY (MCS)
MCS is an acquired disorder characterized by fatigue and a wide range of other
symptoms resembling CFS and Fibromyalgia (FM), which occur as a result of low‐level
chemical exposure.11,12 Although MCS is a controversial and complex condition
with no specific diagnostic tests or criteria, it appears to be related to the ability of the
individual to manage the low‐level exposure to environmental compounds.
13
ENCEPHALOPATHY and PANCREATITIS
These two syndromes share a commonality: patients’ histories include exposure to
xenobiotics, typically various organic solvents and/or their fumes. Chronic toxic
encephalopathy, resulting in lowered detoxification capacity, is more likely to occur
in individuals with a genetic defect in one of the glutathione transferase enzymes.14
In many patients who have been exposed to diesel fumes, paint solvents, or
trichloroethylene, idiopathic pancreatitis can be associated with upregulation of the
Phase I cytochrome P450 enzymes.15
NEUROLOGICAL DISEASES
The combination of genetic susceptibility, reduced detoxification capacity, and increased
exposure to neurotoxins creates the right situation, over time, for development of a clinical
disease. As an example, the impaired ability of some individuals to metabolize sulfur‐containing
xenobiotics may leave them at higher risk for neurotoxicity when exposed to
these types of compounds.16 In fact, this connection has been demonstrated in some cases
of Alzheimer’s, Parkinson’s, and other motor neuron diseases.17,18 Moreover, a detoxification
intervention approach with strong nutritional support was beneficial in cases of early onset
Parkinson’s Disease.19
AUTOIMMUNE DISEASES
Research in recent years suggests a possible role of impaired detoxification in Lupus
erythematosus and rheumatoid arthritis.20
GENETICALLY INDUCED DISORDERS
Gilbert’s Syndrome (GS) is a genetically induced, nutritionally exacerbated metabolic
disorder caused by a malfunction of a key enzyme involved in glucuronidation, a major
Phase II conjugation reaction. Recent observations indicate that patients affected by GS
may be predisposed to bioactivation and potential drug toxicity.
DYSBIOSIS
The many species of beneficial bacteria that reside in the human large intestine produce
endotoxins as the end result of their metabolic activity. In cases where colonic bacteria
become imbalanced, undesirable species that produce damaging metabolites may
appear. The state of imbalance of beneficial organisms in the colon – or dysbiosis –may be caused by the presence of bacterial species such as Klebsiella pneumoniae,
Escherichia coli, and Candida albicans. Studies have suggested the association between
metabolites of fungi and undesirable bacteria residing in the intestine and conditions
such as autism,23 multiple sclerosis, depression, and psychosis.24
HEAVY METAL EXPOSURE
Heavy metals such as lead, mercury, cadmium, arsenic, nickel, and aluminum
accumulate in the body primarily as a result of exposure to a contaminated environment.25
Toxic metals may be present in industrial waste spreading to water, air, and soil. Pipes,
pesticides and cigarette smoke are also common sources of toxic metals. The presence
and consequential accumulation of toxic metals has been demonstrated to result in
neurological impairment, influence neurotransmitter production and utilization, as
well as affect the kidneys and the immune system. Metals can be stored in various
tissues and most likely cause damage to the depot structures of the affected areas.26,27
Additionally, the presence of these heavy metals may lead to impairment of other
detoxification pathways, causing poor elimination of xenobiotics that use these
pathways, and thus intensify their damaging effects. Metals that have nutritive roles
in the body, such as iron, copper, and manganese, may also become toxic at high levels.
해독 기능 진단
유전체 검사(SNP; Single Nucleotide polymorphism)
해독에 관련된 유전자 변이를 조사하여 각 개인의 해독 기능의 생화학적 특이성을 알아보는 주요한 검사로 각종 약물, 음식, 환경 공해 물질에 대한 감수성의 차이를 구별하여 질병 발생의 예방과 치료에 이용한다
해독 관련 유전자
CYP1A1; Cytochrome P450 1A1 의 유전자 변이를 검사하여 phase 1 기능 검사
GSTP1; Glutathione‐S‐Transferase 의 유전자 변이 검사로 phase 2 GSH conjugation 기능 검사
SOD1; Superoxide dismutase 유전자 변이 검사로 항산화 기능을 검사
부하 검사 (CHALLENGE TESTING)
Challenge methods are valuable to assess the “detoxification ability” of an individual, that
is, to evaluate his/her functional capacity to detoxify or respond to a toxic compound. While
these tests are very useful, it is important to remember that:
• no one single test by itself is capable of assessing functional detoxification status,
• the level of toxin and the individual’s unique biochemistry are the two most
important factors in interpreting the results of these determinations.
Challenge tests are ideal non‐invasive tests and are currently the most accepted clinical tools
used to assess functional detoxification. These tests measure the individual’s metabolic capacity
of various detoxification pathways as he/she is challenged with particular compounds called
probe substances. A challenge test involves the oral ingestion of a defined amount of the probe substance, usually a drug with a well‐known detoxification pathway, and the measurement of its metabolites in two or three samples of blood, urine, or saliva taken at specified times.28
Some examples of probe substances are:
Caffeine – used to measure the activity of the CYP1A2 enzyme, which is key for the
detoxification of many environmental toxins such as polyaromatic hydrocarbons in
pesticides, pro‐carcinogens in cigarette smoke, and polyaromatic amines in charbroiled
beef.29,30
Acetaminophen – used to assess the functionality of the glucuronidation and sulfation
conjugation reactions.31 If these pathways are compromised, the acetaminophen is
metabolized through an alternate pathway with the formation of acetaminophen
mercapturate as the end product.
Aspirin – is detoxified by conjugation with glycine (considered to be one of the most
important amino acids in humans),32 and is used to assess the functionality of this
amino acid conjugation reaction. Alternatively, benzoic acid can be used with the same
purpose in subjects with salicylate sensitivity.33
독성 노출 검사(TOXIC LOAD)
ORGANIC COMPOUNDS EXPOSURE
Assessment of exposure to organic compounds can be made by simpIy using a patient
questionnaire. Questions about working and living conditions, as well as lifestyle habits, often
unveil clues about possible sources of direct contact with solvents or exposure to solvent fumes.
Several types of laboratory tests are available to assess specific toxic compounds. For example,
immunological methods are used to test volatile organic compounds such as formaldehyde,
since their hapten‐like actions induce tissue‐specific autoimmune reactions.34
HEAVY METAL ASSESSMENT
Some of the most used tests for presence of toxic metals are:
Hair Analysis – Hair acts as a depot of toxic metals, therefore, its analysis provides
information of element storage over time. Studies have demonstrated correlation
between element hair concentration, environmental exposure, and pathological
effects.35,36 Hair analysis is an excellent indicator of long‐term risk as well as a barometer
for early, chronic exposure, often reflecting excess exposure before symptoms appear.
Hair analysis is a low cost, non‐invasive procedure; the fact that concentrations of
elements in hair are often up to 300 times higher than those of serum or urine make
this an excellent medium for analysis. However, this is still considered a “screening
test” and should be followed by confirmatory testing in blood or urine.
Blood analysis – Due to the effective clearance mechanisms in the blood, the level of
toxic metals in it are usually transient in nature. Therefore, measurement of metal
levels in blood is only informative about what has been recently absorbed (hours or
days). Metals may be analyzed in plasma, serum, or red blood cells.
Urine analysis – Urine is a good indicator of recent exposure to metals (days‐weeks),
showing what the body is currently excreting. “Provocative urine testing” is a special
technique useful to determine toxic element deposition and to monitor its excretion
as a response to treatment. The procedure consists of obtaining a urine sample before
and after administration of a strong excretory inducer, and calculating the amount
of stored toxic elements from the resulting analytical measurements.
BACTERIAL/YEAST/FUNGAL IMBALANCES
Several laboratory techniques are used to determine the presence of abnormal amounts of
potential pathologic bacteria and other organisms. The most commonly used include:
• microbiological identification of potentially pathogenic bacteria and yeast in stool,
• identification of bacterial by‐products: the urine indican (Obermeyer) test estimates
bacterial activity in the small and large intestines by measuring the amount of
indole generated by the bacterial degradation of tryptophan,
• immunological methods to quantify bacterial and yeast antibodies.
해독 기능 이상의 기능영양학적 치료 (4 E program)
• Exposure Decrease
to the toxin source. This is a straightforward approach once the toxin(s) is identified, and it usually involves lifestyle changes.
• Excretion Increase
of the toxin. For example, metal chelation with various agents is used to treat chronic metal intoxication (such as mercury).37,38
• Enhance nutritional support,
either generally or for specific detoxification pathways.
• Establish GI balance
in cases of bacterial flora imbalance, through the use of probiotic and prebiotic supplementation
Exposure Decrease
Life style change(담배,술, 탄음식, 고도 가공 식품, 알러지 유발 음식
절제,운동,명상,마사지,요가,주기적 해독 요법)
Environmental Control(물,공기, 작업,근무환경 개선,천연세제,곰팡이,진균 제거)
Excretion Increase
hepatobiliary flushing
colon cleansing
lymphatic drainage
heavy metal chelation(EDTA,DMPS)
sauna
skin brushing
hydration
deep breathing exercise and yoga
weight reduction(Body fat)
Enhance Nutritional Support
SPECIFIC NUTRITIONAL INTERVENTION
This may be improved by supplementation with specific
nutrients or cofactors:
‐ Impaired sulfation, requiring adequate amounts of dietary sulfur‐containing
compounds such as sulfur‐containing amino acids and inorganic sulfate.39
‐ Impaired glucuronidation, requiring magnesium, and abstention from smoking,
fasting, possibly high fructose intake.
‐ Impaired glutathione conjugation, requiring vitamins B6 and B12, magnesium,
and folate.
‐ Impaired amino acid conjugation, requiring specific amino acids such as
glycine or taurine.
• Inadequate antioxidant support – e.g., in individuals with increased detoxification
Phase I to Phase II ratios. This results in an increased generation of reactive
intermediate metabolites (which are normally generated by the reactions of
Phase I pathways but are readily transformed into soluble molecules by the
conjugation reactions in Phase II pathways).
• Inadequate phytonutrient support for upregulation of Phase II detoxification
activities. For example, the cruciferous vegetable family may provide protection
against carcinogen exposure by inducing glutathione S‐transferase activity.40
Establish GI balance
Gastrointestinal restoration through 4 R program
Especially intestinal dysbiosis correction(pre+ probiotics)
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