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Copy of JM's post on Phase II

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Published: 10 years ago
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Copy of JM's post on Phase II

First, keep in mind that 2200 enzymatic processes are messed up by Lead and Mercury.

There's much more to the article, with the tuberose liver detox information that has been posted here before, and other links. It mainly is about Gilbert's Syndrome, but there's also a good link to more on allergies:

Picking out specific references to enzymes;

The liver plays several roles in detoxification: it filters the blood to remove large toxins, synthesizes and secretes bile full of cholesterol and other fat-soluble toxins, and enzymatically disassembles unwanted chemicals. This enzymatic process usually occurs in two steps referred to as phase I and phase II. Phase I either directly neutralizes a toxin, or modifies the toxic chemical to form activated intermediates which are then neutralized by one of more of the several phase II enzyme systems.

The level of exposure to environmental carcinogens varies widely, as does the efficiency of the detoxification enzymes, particularly phase II. High levels of exposure to carcinogens coupled with slow detoxification enzymes significantly increases susceptibility to cancer.

Currently, over 10 families of Phase I enzymes have been described, which include at least 35 different genes

Phase I detoxification involves a group of enzymes, referred to as the cytochrome P450 family. Some 50-100 enzymes make up the cytochrome P450 systems, with each enzyme working more efficiently at neutralizing certain classes of chemicals

An example of the phase one pathway is the Cytochrome P-450 mixed function oxidase enzyme pathway. These enzymes reside on the membrane system of the liver cells (called Hepatocytes

The family of P-450 enzyme systems is quite diverse, with specific enzyme systems being inducible by particular drugs, toxins or metabolites. It is this characteristic that has allowed the development of special tests to check the function of the various pathways - see liver tests. The substrate is the substance that is acted upon by the enzyme

The liver's third role in detoxification involves a two-step enzymatic process for the neutralization of unwanted chemical compounds. These not only include drugs, pesticides, and toxins from the gut, but also normal body chemicals such as hormones and inflammatory chemicals (e.g. histamine) which become toxic if allowed to build up.

Phase I enzymes directly neutralize some chemicals, but most are converted to intermediate forms that are then processed by phase II enzymes.

Recent research shows that the cytochrome P450 enzyme systems are also found in other parts of the body, especially the brain cells. Inadequate antioxidants and nutrients in the brain result in an increased rate of neuron damage, such as seen in Alzheimer's and Parkinson's disease patients. As with all enzymes, the cytochrome P450s require several nutrients to function, such as copper, magnesium, zinc and vitamin C

The activity of phase I detoxification enzymes decreases in old age

Phase II reactions include sulfation and glucuronidation, which are key to human detoxification, along with glutathione conjugation, methylation, amino acid conjugation, and acetylation. Phase II detoxification typically involves biochemical conjugation, in which various enzymes in the liver attach small chemical moieties to the toxin

Both Phase I and Phase II detoxification require assistance from a healthy supply of enzymes. Enzymes quantity can be influenced by dietary components. Green tea and products found in red wine grapes encourage glucuronidation and glutathione conjugation enzymes, respectively

Glucuronidation, a significant pathway in the Phase II detoxification mechanism, is the combining of glucuronic acid with toxins, a process that requires the enzyme UDP glucuronyl transferase (UDPGT). Foods rich in limonene, a monoterpene found in citrus peel, dill weed oil, and caraway oil, can increase UDPGT activity and encourage the glucuronidation mechanism

The phase two enzyme systems include both UDP-glucuronyl transferase (GT) and glutathione-S-transferase (GSH-T). Glutathione is the most powerful internal antioxidant and liver protector.

Phase II detoxification typically involves conjugation in which various enzymes in the liver attach small chemicals to the toxin. This conjugation reaction either neutralizes the toxin or makes the toxin more easily excreted through the urine or bile. Phase II enzymes act on some toxins directly, while others must first be activated by the phase I enzymes. There are essentially six phase II detoxification pathways:

· Glutathione conjugation
· Amino acid conjugation
· Methylation
· Sulfation
· Acetylation
· Glucuronidation

In order to work, these enzyme systems need nutrients both for their activation and to provide the small molecules they add to the toxins. In addition, they utilize metabolic energy to function and to synthesize some of the small conjugating molecules. Thus, mitochondrial dysfunction, such as found in chronic fatigue syndrome, a magnesium deficiency or physical inactivity, can cause phase II detoxification to slow down, allowing the build-up of toxic intermediates

Nutrients needed by phase II detoxification enzymes

Glutathione conjugation: Glutathione, vitamin B6
Amino acid conjugation: Glycine
Methylation: S-adenosyl-methionine
Sulfation: Cysteine, methionine, molybdenum
Acetylation: Acetyl-CoA
Glucuronidation: Glucuronic acid

Inducers of Phase II Detoxification Enzymes

Note: The term "induce" can be misleading as it refers to anything that fires up the system - those that are harmful which need processing, and those which arent harmful and activate processing.

Glutathione conjugation: Brassica family foods (cabbage, broccoli, Brussels sprouts); limonene-containing foods (citrus peel, dill weed oil, caraway oil)
Amino acid conjugation: Glycine
Methylation: Lipotropic nutrients (choline, methionine, betaine, folic acid, vitamin B12)
Sulfation: Cysteine, methionine, taurine
Acetylation: None found
Glucuronidation: Fish oils, cigarette smoking, birth control pills, Phenobarbital, limonene-containing foods

Inhibitors of Phase II Detoxification Enzymes

Note: Inhibition of phase II detoxification is not desired, especially in those with Gilbert's Syndrome, as these enzymes are already inhibited.

Glutathione conjugation: Selenium deficiency, vitamin B2 deficiency, glutathione deficiency, zinc deficiency
Amino acid conjugation: Low protein diet
Methylation: Folic acid or vitamin B12 deficiency
Sulfation: Non-steroidal anti-inflammatory drugs (e.g. aspirin), tartrazine (yellow food dye), molybdenum deficiency
Acetylation: Vitamin B2, B5, or C deficiency
Glucuronidation: Aspirin, probenecid

Glucuronidation, the combining of glucuronic acid with toxins, requires the enzyme UDP-glucuronyl transferase (UDPGT).

Glucuronidation appears to work well, except for those with Gilbert's syndrome--a relatively common syndrome characterized by a chronically elevated serum bilirubin level

The activity of UDPGT is increased by foods rich in the monoterpene limonene (citris peel, dill weed oil, and caraway oil).

Methionine, administered as SAM, has been shown to be quite beneficial in treating Gilbert's syndrome

The body has a two-phase detoxification system. Depending on the toxin, the first phase can either detoxify it entirely or prepare it for the second phase. In the second phase there are several major systems which act on these toxins. The one affected by Gilbert's Syndrome is the glucuronidation system, which "conjugates" the toxins so they can be removed from the body. Enzymes in the glucuronidation system are called uridine diphosphate glucuronyl transferase, or UGT for short. UGT1A1, for example, refers to a specific enzyme in this family.

Gilbert's syndrome is due to a genetic mutation that causes only 30% of the enzyme UGT1A1 to be produced. This is the only enzyme that detoxifies bilirubin, a toxic product of the natural breakdown of red blood cells. This enzymatic shortage leads to an excess of bilirubin (and other toxins) in the blood serum. Most people with Gilbert's Syndrome also have linked mutations in two other enzymes - UGT1A6 and UGT1A7, causing similar enzyme shortages which leads to their related toxins circulating in the body for longer periods as well. The things acted upon by these enzymes include many carcinogens, drugs, hormones, and various other toxins

Gilbert’s Syndrome (GS) is a genetic and therefore inherited condition which is characterized by a defect in the Phase II detoxification enzyme UDP-Glucuronyl transferase (UDPGT) which is responsible for the glucuronidation detoxification pathway in the liver. People who have this condition are inefficient in detoxifying and conjugating both endogenous and exogenous toxins which require the glucuronidation pathway for elimination from the body. One endogenous component which requires this pathway is bilirubin which has been discussed above. New research is showing that glucuronidation is an important detoxification pathway for many other substances and that individuals who have this disorder are more susceptible to toxic reactions to xenobiotics and drugs


Other liver enzymes:

Glutathione-S-transferase detoxifies many water-soluble environmental toxins, including many solvents, herbicides, fungicides, lipid peroxides, and heavy metals (e.g., mercury, cadmium, and lead). The various forms of GST work together to eliminate toxins. Decreased glutathione conjugation capacity may incrase toxic burden and increase oxidative stress

Most of the methyl groups used for detoxification come from S-adenosylmethionine (SAM). SAM is synthesized from the amino acid methionine, a process which requires the nutrients choline, vitamin B12, and folic acid. SAM is able to inactivate estrogens (through methylation),

Catechol-O-methyl transferase is the enzyme primarily responsible for breaking down the neurotransmitters dopamine, epinephrine, and norepinephrine.

N-acetyl Transferase detoxifies many environmental toxins

People with a very active phase I detoxification system coupled with slow or inactive phase II enzymes are termed pathological detoxifiers. These people suffer unusually severe toxic reactions to environmental poisons

Key Liver Functions
The liver is the body’s largest organ, weighing three to five pounds in adults. Optimal nutrition is a function not just of what we eat and digest, but of how well the liver transforms incoming nutrients into the proper biochemical forms your cells need to perform their metabolic functions. Some of the liver’s key functions:

• Converts the thyroid hormone thyroxine (T4) into it more active form triiodothyronine (T3). Inadequate conversion may lead to hypothyroidism, chronic fatigue, weight gain, poor memory and other debilitating conditions.
• Creates GTF (Glucose Tolerance Factor) from chromium, niacin and possibly glutathione. GTF is needed for the hormone insulin to properly regulate blood-sugar levels. Manufactures bile salts which emulsify fats and the fat-soluble vitamins A, D, E, and K for proper absorption. The liver also removes some fat-soluble toxins from the body.
• Activates B vitamins into their biologically active coenzyme forms. Virtually every nutrient must be biotransformed by the liver into its proper biochemical form before the nutrient can be stored, transported or used in cellular metabolism.
• Stores various nutrients, especially A, D, B-12 and iron for release as needed.
• Manufactures carnitine from lysine and other nutrients. Carnitine is the only known bionutrient which can escort fats into the mitochondria where they are used to generate ATP energy. The mitochondria generate 90% of the ATP energy at the cellular level.
• Converts lactic acid from a toxic waste to an important storage fuel. Lactic acid is produced when glucose is metabolized through the energy production cycle. When excessive levels accumulate, you experience sore muscles. A healthy liver will extract lactic acid from the bloodstream and convert it into the reserve endurance fuel, glycogen.
• Serves as the main glucose buffer, preventing high or low extremes of blood sugar. The liver is the key regulator of blood Sugar between meals due to its manufacture, storage, and release of glycogen, the starch form of glucose. When blood Sugar is low, a healthy liver converts stored glycogen into glucose, releasing it into the bloodstream to raise blood Sugar levels. When blood sugar is high, a healthy liver will convert the excess into stored glycogen or fat.
• Chief regulator of protein metabolism. The liver converts different amino acids into each other as needed.
• Produces cholesterol and converts it into the various forms needed for blood transport.
• Converts essential fatty acids such as GLA, EPA, and DHA into the lipoprotein forms necessary to allow transport via the bloodstream to the 50 trillion cells requiring fatty acids.
• Main poison-detoxifying organ in the body. The liver must break down every substance toxic to the body including metabolic wastes, insecticide and pesticide residues, drugs, alcohol, etc. Failure of this function will usually cause death in 12 to 24 hours.
• Removes ammonia, a toxic by-product of animal protein metabolism, from the body.
• Breaks down hormones after they have served their function. i.e., if the liver does not break down insulin fast enough, hypoglycemia results because the circulating insulin continues to lower blood sugar.

Note: The explanatory power of a sluggish overall liver is quite strong. This has the ability to explain fatigue, tiredness, hypoglycemia, reactive hypoglycemia, muscle soreness, and possibly the mental effects due to slower detoxification - brain fog, poor memory, difficulty concentrating, difficulty finding the right words. Plus the hypothyroid effects of low T3 levels can cause many of the related problems.


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