Phases of detoxification

The detoxification process in the body is composed of two phases, known as Phase I and Phase II. These phases are two different biochemical processes that enable the body to eliminate xenobiotics and other chemicals.

Phase I detoxification

This phase of detoxification changes nonpolar, nonwater-soluble chemicals into relatively polar (electrically charged) compounds with the help of enzymes that add a polar or reactive group. Phase I detoxification prepares the chemical so that a small molecule can be added or modified during Phase II, which will make the chemical water-soluble, allowing it to be excreted naturally by the body. The changes in Phase I constitute a type of chemical reaction known as biotransformation. Typical changes that occur to most chemicals include:

1. Oxidation reactions (electrons are lost)

• Dehalogenation: Eliminates a halogen group (containing fluorine, chlorine, bromine, or iodine) and adds an oxygen group
• Desulfuration: Eliminates a sulfur group
• Hydroxylation: Adds a hydroxyl (oxygen and hydrogen) group
• Deamination: Removes an amino group (nitrogen and hydrogen combined as NH3)
• Sulfoxidation: Adds an oxygen to a sulfur group

2. Reduction reactions (electrons are gained)

• Azo reduction: Splits a nitrogen-to-nitrogen (N2) bond
• Reductive halogenation: Replaces a halogen group with hydrogen
• Aromatic nitro reduction: Converts nitrogen dioxide (NO2) to an amide (NH2)
• Aldehyde and ketone reduction: Converts aldehydes and ketones (organic chemical compounds) to an alcohol

At least 50 enzymes in 10 families governed by 35 different genes allow Phase I to take place. The major enzymes required during Phase I are known as the cytochrome P-450 monooxygenase system and the mixed-function amine oxidase system. The primary system is the cytochrome P-450 monooxygenase system, which catalyzes and initiates the Phase I processes. The mixed-function amine oxidase system detoxifies chemical groups called amines, which contain nitrogen and hydrogen.

Many forms of cytochrome P-450 enzymes are involved in Phase I reactions. The highest concentration of cytochrome P-450 occurs in the liver, which is the most active site of metabolism. The lungs and the kidneys are secondary organs of biotransformation, with about one-third of the liver's detoxification capacity. Cytochrome P-450 has also been found in the intestines, adrenal cortex, testes, spleen, heart, muscles, brain, and skin.

The action of detoxification enzymes depends on the presence of various minerals. For example, alcohol dehydrogenase, an enzyme that converts alcohols (such as ethanol) to aldehydes in an oxidation reaction, depends on an adequate supply of zinc to function properly. In the next metabolic step, the enzyme aldehyde oxidase changes the aldehyde into an acid that can be excreted in the urine. Aldehyde oxidase depends on an adequate supply of molybdenum and iron. Other minerals that are required by enzymes include manganese, magnesium, sulfur, selenium, and copper.

Usually, the enzymatic reactions in Phase I decrease chemical toxicity. However, toxic or reactive chemicals can form during Phase I that are more toxic than the original compound. This is known as bioactivation. When Phase II detoxification proceeds normally, these chemicals are then rendered harmless and excreted. However, if there is an imbalance in the active levels of Phase I and II detoxification, these toxins will remain in the body. Imbalance between Phase I and Phase II is associated with increased symptoms of nervous, immune, and endocrine system toxicity.

Toxic chemicals produced during Phase I include teratogens (causing fetus malformation), mutagens (causing cell mutation), and carcinogens (causing cancer). For example, benzo[a]pyrene, a chemical found in coal tar and cigarette side stream smoke, is biologically inert until it is converted by the mixed-function amine oxidase system into a metabolite that can then initiate cancer causing activity. During Phase I, many compounds also form dangerous reactive free radicals -chemicals with an unpaired electron that can cause tissue damage. A buildup of free radicals can increase the risk of cancer.

The level of functioning of Phase I can be measured with a simple caffeine metabolism test. A known quantity of caffeine is ingested, and saliva samples are taken twice at specified intervals. The efficiency of caffeine clearance is directly related to the efficiency of Phase I detoxification. Rapid clearance of caffeine shows enzyme induction (increased production), either from xenobiotic exposure or toxins within the body. A slow rate of caffeine clearance indicates that cytochrome P-450 activity in the liver is abnormal. Patients with slow caffeine clearance have difficulty eliminating xenobiotics and other toxins.

Phase II detoxification

In Phase II detoxification, chemical groups are added, or conjugated, to the chemical. The chemical becomes water-soluble and can be excreted through the kidneys, or, if the chemical is of high molecular weight, through the bile. If a xenobiotic already has a chemical group on the molecule that is suitable for a Phase II reaction, Phase I is not required. The xenobiotic is detoxified directly by Phase II conjugation.

Major conjugation reactions include:

• Acetylation: Acetyl Co-A (coenzyme A and acetic acid) is added to form a mercapturic acid conjugate; this is the chief detoxification/transformation pathway for amines and amides (organic compounds containing nitrogen). Needs B5 to function. Can be adversely affected by pollutant overload and enzyme deficiency, either acquired or genetic.
• Amino acid conjugation (acylation): Peptide (compound formed by two amino acids linked by a special bond) conjugation using acyl Co-A (coenzyme A and carboxylic acid) and the amino acids taurine, glycine, glutamine, and to a lesser extent, arginine and ornithine. Glycine is the most commonly used amino acid. Glutamine is important in ammonia detoxification. This conjugation forms hippuric acid, which is excreted in the kidneys and can be measured.
• Glucuronidation (gluconation): Addition of a sugar group, using glucuronic acid; the major conjugation reaction for xenobiotics and internally produced chemicals converting them to water-soluble metabolites. Acts on certain pharmaceuticals; coal tar derivatives; dyes; phenols; excess vitamins D, E, and K; melatonin hormones; bile salts; bilirubin; steroid hormones; and estrogen.
• Glutathione conjugation: Reduced glutathione combines with xenobiotics to form less toxic compounds. Plays a major role in conjugating reactive metabolites formed during cytochrome P-450 biotransformation. Predominant defense against free radicals. Results in formation of mercapturic acid.
• Methylation: Addition of a methyl (CH3) group, using the amino acid methionine to supply the methyl group. Detoxifies many synthetics and endogenous toxic compounds; the neurotransmitters epinephrine, norepinephrine, and serotonin; and nutrients. This reaction is B6 dependent.
• Sulfur conjugation (sulfation ): Includes several processes including sulfonation, which adds inorganic sulfate to hydroxyl groups for detoxification, and reduction of cyanides by adding sulfur. Is involved in detoxification of drugs, food additives, certain environmental pollutants, steroid and thyroid hormones, heavy metals, and monoamine neurotransmitters. Requires more energy than other conjugation reactions and will not take place when energy is low.

The function of Phase II can be evaluated through the ingestion of both acetaminophen and aspirin. This test measures the recovery of the products of glutathione conjugation, sulfur conjugation, glucuronidation, and glycine conjugation (acylation) in the urine. Comparison to normal values allows evaluation of the efficiency of Phase II. A high ratio between Phase I and any of the Phase II pathways implies imbalanced detoxification in the body.

Rates of detoxification

The efficiency of Phase I and Phase II is adversely affected by deficiencies of vitamins, minerals, amino acids, and fatty acids. Inadequate protein intake specifically reduces Phase I clearance, and insufficient calories decreases overall detoxification function. In addition, these processes can be affected by foreign chemicals for which the body has no detoxifying mechanisms, poisoning of detoxification enzymes by heavy metals, toxic overload from overwhelming exposures, and a deficiency of detoxification enzymes due to genetic inheritance.

The detoxification process requires large amounts of caloric energy, which comes mainly from the food we eat. If we do not eat enough protein, the body breaks down vital tissue protein to produce the energy it needs. This decreases the available amounts of Phase I and Phase II enzymes, amino acids, and peptides, because the body breaks down protein to amino acids and peptides. The greater the toxic burden of the body, the higher the need for protein, carbohydrate, fat, and micronutrient intake.

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• DETOXIFICATION
  • Early methods of detoxification
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  • Responses to toxins
  • Organs of protection and detoxification
  • Organ cleansing
  • Detoxification baths
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  • Detoxification diet, fasting, & juicing
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  • Detoxification herbs
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