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Gilbert's Syndrome | The Detoxification System | Understanding the Mutations | GS Symptoms | Things That Help & Things To Avoid
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The Detoxification System


Contents: Detoxification | Phase I Detoxification Pathways | Phase II Detoxification Pathways | Imbalances Between Phase I and II

This is a work in progress and is being updated regularly. Check back regularly, as I will be steadily improving the site and adding more information.

 

Detoxification (The Liver)

http://www.lef.org/protocols/prtcl-143a.shtml

The detoxification process is an elaborate mechanism conducted chiefly by the liver to eliminate both exogenous and endogenous toxins. The liver participates in the detoxification process, largely by the action of two sequential steps referred to as Phase I and Phase II systems. Phase I reactions involve blood filtration, bile excretion, and the interaction of enzymatic processes acting upon the toxin. Bile excretion is most efficient, in regard to the detoxification process, if adequate amounts of dietary fiber are simultaneously available to escort the toxin from the intestines.

Ideally, Phase I and Phase II detoxification mechanisms work synergistically. If Phase I detoxification is highly active and Phase II detoxification is lethargic, the individual is referred to as a "pathological detoxifier," a condition which increases sensitivities to environmental poisons. (I also quoted this below)

http://www.somis.dundee.ac.uk/staffprofiles/d/2000120700/

Chemical defence is achieved by detoxification of compounds in the body and is generally considered a two step process; phase I metabolism includes oxidation, reduction, hydration, hydrolysis, isomerization and other specific reactions. In general, the products of phase I reaction are more chemically reactive than the parent compound, and phase I is seen as the creation of a reactive species prior to true detoxification by phase II metabolism. In phase II metabolism the substrate is conjugated to a polar hydrophobic group rendering the aglycone more water soluble and suitable for excretion.

http://tuberose.com/Liver_Detoxification.html

The liver is one of the most important organs in the body when it comes to detoxifying or getting rid of foreign substances or toxins. The liver plays a key role in most metabolic processes, especially detoxification. The liver neutralizes a wide range of toxic chemicals, both those produced internally and those coming from the environment. The normal metabolic processes produce a wide range of chemicals and hormones for which the liver has evolved efficient neutralizing mechanisms. However, the level and type of internally produced toxins increases greatly when metabolic processes go awry, typically as a result of nutritional deficiencies. These non-end-product metabolites have become a significant problem in this age of conventionally grown foods and poor diets.

Many of the toxic chemicals the liver must detoxify come from the environment: the content of the bowels and the food, water, and air. The polycyclic hydrocarbons (DDT, dioxin, 2,4,5-T, 2,3-D, PCB, and PCP), which are components of various herbicides and pesticides, are on example of chemicals that are now found in virtually all fat tissues measured. Even those eating unprocessed organic foods need an effective detoxification system because all foods contain naturally occurring toxic constituents.

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.

Proper functioning of the liver's detoxification systems is especially important for the prevention of cancer. Up to 90% of all cancers are thought to be due to the effects of environmental carcinogens, such as those in cigarette smoke, food, water, and air, combined with deficiencies of the nutrients the body needs for proper functioning of the detoxification and immune 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.

Filtering the Blood

One of the liver's primary functions is filtering the blood. Almost 2 quarts of blood pass through the liver every minute for detoxification. Filtration of toxins is absolutely critical as the blood from the intestines contains high levels of bacteria, bacterial endotoxins, antigen-antibody complexes, and various other toxic substances. When working properly, the liver clears 99% of the bacteria and other toxins during the first pass. However, when the liver is damaged, such as in alcoholics, the passage of toxins increases by over a factor of 10.

Bile Excretion

The liver's second detoxification process involves the synthesis and secretion of bile. Each day the liver manufactures approximately 1 quart of bile, which serves as a carrier in which many toxic substances are dumped into the intestines. In the intestines, the bile and its toxic load are absorbed by fiber and excreted. However, a diet low in fiber results in inadequate binding and reabsorption of the toxins. This problem is magnified when bacteria in the intestine modify these toxins to more damaging forms.

http://www.chiro.org/nutrition/ABSTRACTS/Detoxification_Enzyme_Systems.shtml

Currently, over 10 families of Phase I enzymes have been described, which include at least 35 different genes. Phase II reactions are equally complex, and involve multiple gene families as well.

A good picture of the whole system: http://www.chiro.org/nutrition/FULL/Detoxification_Fig2.jpg


 

Phase I Detoxification Pathways

http://www.lef.org/protocols/prtcl-143a.shtml

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. Phase I enzymes can directly neutralize some chemicals, but most toxins are converted to an intermediate form of the toxin. The intermediate form is considered more toxic than the original and requires the action of Phase II detoxification to complete the cycle.

http://www.liverdoctor.com/03_detoxpathways.asp

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).

Human liver cells possess the genetic code for many isoenzymes of P-450 whose synthesis can be induced upon exposure to specific chemicals. This provides a mechanism of protection from a wide variety of toxic chemicals.

To put it simply, this pathway converts a toxic chemical into a less harmful chemical. This is achieved by various chemical reactions (such as oxidation, reduction and hydrolysis), and during this process free radicals are produced which, if excessive, can damage the liver cells. Antioxidants (such as vitamin C and E and natural carotenoids) reduce the damage caused by these free radicals. If antioxidants are lacking and toxin exposure is high, toxic chemicals become far more dangerous. Some may be converted from relatively harmless substances into potentially carcinogenic substances.

Excessive amounts of toxic chemicals such as pesticides can disrupt the P-450 enzyme system by causing over activity or what is called 'induction' of this pathway. This will result in high levels of damaging free radicals being produced.

Substances that may cause overactivity (or induction) of the P- 450 enzymes:

Caffeine, Alcohol, Dioxin, Saturated fats, Organophosphorus pesticides, Paint fumes, Sulfonamides, Exhaust fumes, Barbiturates

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.

Substrates of cytochrome P-450 enzymes:

Theophylline, caffeine, phenacetin, acetaminophen, Lidocaine, erythromycin, cyclosporin, ketoconazole, testosterone, estradiol, cortisone, Alprenolol, bopindolol, carvedilol, metoprolol, propranolol , Amitriptyline, clomipramine, desipramine, nortriptyline , Codeine, dextrometh- orphan, ethylmorphine, 4-methoxyamphetamin Family Phenytoin, ibuprofen, naproxen, oxicam drugs, S-warfarin, Diazepam, hexobarbitone, imipramine, omeprazole, alcohol, chlorzoxazone, enflurane.

http://tuberose.com/Liver_Detoxification.html

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. These intermediate forms are much more chemically active and therefore more toxic. If the phase II detoxification systems are not working adequately, these intermediates can cause substantial damage, including the initiation of carcinogenic processes.

Phase I detoxification of most chemical toxins involves a group of enzymes which, collectively, have been named cytochrome P450. Some 50-100 enzymes make up the cytochrome P450 system. Each enzyme works best in detoxifying certain types of chemicals, but with considerable overlap in activity among the enzymes.

The activity of the various cytochrome P450 enzymes varies significantly from one individual to another, based on genetics, the individual's level of exposure to chemical toxins, and his or her nutritional status. Since the activity of cytochrome P450 varies so much, so does an individual's risk for various diseases. This variability of cytochrome P450 enzymes is seen in the variability of people's ability to detoxify the carcinogens found in cigarette smoke and helps to explain why some people can smoke with only modest damage to their lungs, while others develop lung cancer after only a few decades of smoking.

Patients with underactive phase I detoxification will experience caffeine intolerance, intolerance to perfumes and other environmental chemicals, and an increased risk for liver disease, while those with an overactive system will be relatively unaffected by caffeine drinks. One way of objectively determining the activity of phase I is to measure how efficiently a person detoxifies caffeine. Using this test, a surprising fivefold difference in the detoxification rates of apparently healthy adult has been discovered.

When cytochrome P450 metabolizes a toxin, it chemically transforms it to a less toxic form, makes it water-soluble, or converts it to a more chemically active form. Caffeine is an example of a chemical directly neutralized by phase I. Making a toxin water-soluble allows its excretion by the kidneys. Transforming a toxin to a more chemically reactive form makes it more easily metabolized by the phase II enzymes.

A significant side-effect of phase I detoxification is the production of free radicals as the toxins are transformed--for each molecule of toxin metabolized by phase I, one molecule of free radical is generated. Without adequate free radical defenses, every time the liver neutralizes a toxin exposure, it is damaged by the free radicals produced.

The most important antioxidant for neutralizing the free radicals produced in phase I is glutathione. In the process of neutralizing free radicals, however, glutathione (GSH) is oxidized to glutathione disulfide (GSSG). Glutathione is required for one of the key phase II detoxification processes. When high levels of toxin exposure produce so many free radicals from phase I detoxification that the glutathione is depleted, the phase II processes dependent upon glutathione stop.

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. A considerable amount of research has found that various substances activate cytochrome P450 while others inhibit it.

http://www.chiro.org/nutrition/ABSTRACTS/Detoxification_Enzyme_Systems.shtml

Good picture of Phase I activities: http://www.chiro.org/nutrition/FULL/Detoxification_Tab2.jpg

Good picture of Phase I enzymes: http://www.chiro.org/nutrition/FULL/Detoxification_Fig3.jpg

Inducers of Phase I Detoxification

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.

http://tuberose.com/Liver_Detoxification.html

Cytochrome P450 is induced by some toxins and by some foods and nutrients. Obviously, it is beneficial to improve phase I detoxification in order to eliminate toxins as soon as possible. This is best accomplished by providing the needed nutrients and non-toxic stimulants while avoiding those substances that are toxic. However, stimulation of phase I is contraindicated if the patient's phase II systems are underactive.

Drugs and environmental toxins activate P450 to combat their destructive effects, and in so doing, not only use up compounds needed for this detoxification system but contribute significantly to free radical formation and oxidative stress. Among foods, the brassica family, i.e. cabbage, broccoli, and Brussels sprouts, contains chemical constituents that stimulate both phase I and phase II detoxification enzymes. One such compound is indole-3-carbinol, which is also a powerful anti-cancer chemical. It is a very active stimulant of detoxifying enzymes in the gut as well as the liver. The net result is significant protection against several toxins, especially carcinogens. This helps to explain why consumption of cabbage family vegetables protects against cancer.

Oranges and tangerines (as well as the seeds of caraway and dill) contain limonene, a phytochemical that has been found to prevent and even treat cancer in animal models. Limonene's protective effects are probably due to the fact that it is a strong inducer of both phase I and phase II detoxification enzymes that neutralize carcinogens.

Drugs: alcohol; nicotine in cigarette smoke; Phenobarbital; sulfonamides; steroids
Foods: cabbage, broccoli, and brussels sprouts; charcoal-broiled meats; high-protein diet; oranges and tangerines (but not grapefruits)
Nutrients: niacin; vitamin B1; vitamin C
Herbs: caraway and dill seeds
Environmental toxins: carbon tetrachloride; exhaust fumes; paint fumes; dioxin; pesticides

Inhibitors of Phase I Detoxification

Note: In general, inhibition of detoxification is not desired. In the case of Gilbert's Syndrome, there is an exception to Phase 1 inhibitors, as at a certain level it can allow Phase II detox to keep up with it.

http://tuberose.com/Liver_Detoxification.html

Many substances inhibit cytochrome P450. This situation can cause substantial problems as it makes toxins potentially more damaging because they remain in the body longer before detoxification. For example, grapefruit juice decreases the rate of elimination of drugs from the blood and has been found to substantially alter their clinical activity and toxicity. Eight ounces of grapefruit juice contains enough of the flavonoid naringenin to decrease cytochrome P450 activity by a remarkable 30%.

Curcumin, the compound that gives turmeric its yellow color, is interesting because it inhibits phase I while stimulating phase II. This effect can be very useful in preventing certain types of cancer. Curcumin has been found to inhibit carcinogens, such as benzopyrene (found in charcoal-broiled meat), from inducing cancer in several animal models. It appears that the curcumin exerts its anti-carcinogenic activity by lowering the activation of carcinogens while increasing the detoxification of those that are activated. Curcumin has also been shown to directly inhibit the growth of cancer cells. As most of the cancer-inducing chemicals in cigarette smoke are only carcinogenic during the period between activation by phase I and final detoxification by phase II, curcumin in the turmeric can help prevent the cancer-causing effects of tobacco. Those exposed to smoke, aromatic hydrocarbons, and other environmental carcinogens will probably benefit from the frequent use of curry or turmeric.

The activity of phase I detoxification enzymes decreases in old age. Aging also decreases blood flow through the liver, further aggravating the problem. Lack of the physical activity necessary for good circulation, combined with the poor nutrition commonly seen in the elderly, add up to a significant impairment of detoxification capacity, which is typically found in aging individuals. This helps to explain why toxic reactions to drugs are seen so commonly in the elderly.

Drugs: benzodiazepines; antihistamines; cimetidine and other stomach-acid secretion blocking drugs; ketoconazole; sulfaphenazole

Foods: naringenin from grapefruit juice; curcumin from turmeric; capsaicin form chili pepper; eugenol from clove oil; quercetin from onions

Botanicals: curcuma longa (curcumin); capsicum frutescens (capsaicin); eugenia caryophyllus (eugenol); calendula officianalis

Other: aging; toxins from inappropriate bacteria in the intestine


 

Phase II Detoxification Pathways

http://www.lef.org/protocols/prtcl-143a.shtml

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. The conjugation reaction neutralizes toxins and reactive intermediates left over from Phase I detoxification. Both Phase I and Phase II detoxification require assistance from a healthy supply of enzymes. Enzyme 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.

Many commonly used substances--for example, aspirin, menthol, synthetic vanilla, acetaminophen, morphine, diazepam, digitalis, benzoates, and some hormones--are detoxified through the glucuronidation pathway. Beta-glucuronidase, regarded as a dangerous enzyme, interferes with the glucuronidation process, allowing toxic levels of drugs and contaminants to accumulate. Older individuals appear particularly susceptible to increased beta-glucuronidase formation because of long-term exposure to toxic agents.

Murray et al. (1998) report that the glucuronidation pathway is also impaired in the 5% of the population with Gilbert's syndrome. Gilbert's syndrome is a benign hereditary condition characterized by hyperbilirubinemia (serum bilirubin level 1.2-3.0 mg/dL) and jaundice. The Gilbert's syndrome patient typically complains of loss of appetite, malaise, and fatigue, symptoms often identifiable with liver dysfunction.

http://www.liverdoctor.com/03_detoxpathways.asp

This is called the conjugation pathway, whereby the liver cells add another substance (eg. cysteine, glycine or a sulphur molecule) to a toxic chemical or drug, to render it less harmful. This makes the toxin or drug water-soluble, so it can then be excreted from the body via watery fluids such as bile or urine.

Major Phase II pathways include glutathione, sulfate, glycine, and glucuronide conjugations. Individual xenobiotics and metabolites usually follow one or two distinct pathways. Again, this makes testing of the various pathways possible by challenging with known substances.

The conjugation molecules are acted upon by specific enzymes to catalyse the reaction step. Through conjugation, the liver is able to turn drugs, hormones and various toxins into excretable substances. For efficient phase two detoxification, the liver cells require sulphur-containing amino acids such as taurine and cysteine. The nutrients glycine, glutamine, choline and inositol are also required for efficient phase two detoxification. Eggs and cruciferous vegetables (eg. broccoli, cabbage, Brussels sprouts, cauliflower), and raw garlic, onions, leeks and shallots are all good sources of natural sulphur compounds to enhance phase two detoxification. Thus, these foods can be considered to have a cleansing action. 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. It can be depleted by large amounts of toxins and/or drugs passing through the liver, as well as starvation or fasting. Phase II reactions may follow Phase I for some molecules or act directly on the toxin or metabolite.

http://www.chiro.org/nutrition/ABSTRACTS/Detoxification_Enzyme_Systems.shtml

Good picture of Phase II conjugation reactions: http://www.chiro.org/nutrition/FULL/Detoxification_Tab3.jpg

http://tuberose.com/Liver_Detoxification.html

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.

http://tuberose.com/Liver_Detoxification.html

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.

http://tuberose.com/Liver_Detoxification.html

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 Pathway

http://www.somis.dundee.ac.uk/staffprofiles/d/2000120700/

Glucuronidation is a major phase II detoxification pathway in which the sugar moiety of UDP-glucuronic acid is covalently linked to a xenobiotic or endobiotic, facilitating its removal from the body in the urine or bile. The directed excretion of glucuronides from the lumen of the endoplasmic reticulum (ER) to the plasma membrane and the exterior of the cell is an important regulated process. Impaired excretion leads to liver damage. Specific transporters for excretion of glucuronides have been implicated in lever cell function in ER and bile canaliculus.

http://www.liverdoctor.com/03_detoxpathways.asp

Polycyclic aromatic hydrocarbons, steroid hormones, some nitrosamines, heterocyclic amines, some fungal toxins, and aromatic amines. It also removes "used" hormones, such as estrogen and T4 (thyroid hormone) that are produced naturally by the body.

http://tuberose.com/Liver_Detoxification.html

Glucuronidation, the combining of glucuronic acid with toxins, requires the enzyme UDP-glucuronyl transferase (UDPGT). Many of the commonly prescribed drugs are detoxified through this pathway. It also helps to detoxify aspirin, menthol, vanillin (synthetic vanilla), food additives such as benzoates, and some hormones. Glucuronidation appears to work well, except for those with Gilbert's syndrome--a relatively common syndrome characterized by a chronically elevated serum bilirubin level (1.2-3.0 mg/dl). Previously considered rare, this disorder is now known to affect as much as 5% of the general population. The condition is usually without serious symptoms, although some patients do complain about loss of appetite, malaise, and fatigue (typical symptoms of impaired liver function). The main way this condition is recognized is by a slight yellowish tinge to the skin and white of the eye due to inadequate metabolism of bilirubin, a breakdown product of hemoglobin. 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

http://www.answers.com/main/ntquery;jsessionid=2bawkmhkcb1np?method=4&dsid=2222&dekey=Glucuronidation&curtab=2222_1&sbid=lc05b

Glucuronidation is a major inactivating pathway for a huge variety of exogenous and endogenous molecules, including drugs, polluants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids and bile acids.

The Glucuronidation Subfamilies

http://carcin.oxfordjournals.org/cgi/content/full/22/7/1087

N-Glucuronidation of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) and N-hydroxy-PhIP by specific human UDP-glucuronosyltransferases
 
Glucuronidation has been well established as a major conjugation reaction in the biotransformation of many xenobiotics. These conjugation reactions are catalyzed by numerous isoforms of UDP-glucuronosyltransferase (UGT) (1). These enzymes are primarily found in the endoplasmic reticulum of many tissues, with the liver being, quantitatively, the most significant site of glucuronidation. In addition to a wide tissue distribution of UGTs, different isozymes can be preferentially expressed in specific tissues. Furthermore, polymorphic expression of certain UGTs has also been observed (2). Three UGT families have been identified in humans; designated UGT1, UGT2 and UGT8 based on their evolutionary divergence (1). Of these three families UGT1 and UGT2 have been shown to catalyze the glucuronidation of a wide variety of xenobiotic substrates, with UGT1 being more active in the glucuronidation of amines (3,4). Aryl- and alkylamines, sulfonamides, heterocyclic amines and hydroxylated compounds have all been reported to undergo glucuronidation in many animal species and humans. The primary function of UGTs is to eliminate substrates from the body via urine and feces by catalyzing the formation of hydrophilic glucuronide conjugates (5).

In Short: UGT detoxifies many xenobiotics. The UGT1 family specializes in processing amines, arylamines and alkylamines, sulfonamides, heterocyclic amines and hydroxylated compounds.

SCIENCE: PDF

UGT pharmacogenomics: implications for cancer risk and cancer therapeutics

UDP-glucuronosyltransferases (UGTs) belong to a superfamily of microsomal enzymes responsible for glucuronidation of numerous endogenous and exogenous compounds including bilirubin, hormones, various drugs as well as environmental carcinogens. Glucuronidation predominantly serves as a pathway for elimination of the different glucuronidated compounds. Seventeen human UGT transcripts have been identified thus far, and the UGT proteins are differentially expressed in a wide-range of human tissues.

Most of the UGTs are expressed in the liver as well as other extrahepatic tissues; however, some are exclusively extrahepatic (Table 1). The tissue specific regulation of UGTs ensures a unique complement of UGT proteins to various tissues, and defines the capacity of each tissue's ability to eliminate or inactivate various exogenous and endogenous substrates.

Table 1 UGT expression in human tissues
UGT isoform Tissue expression References
UGT1A1 Biliary tissue, colon, intestine, liver, stomach Reviewed in 1 and 6
UGT1A3 Biliary tissue, colon, liver, stomach Reviewed in 1
UGT1A4 Biliary tissue, colon, intestine, liver Reviewed in 1and 6
UGT1A5 Not detected  
UGT1A6 Biliary tissue, brain, colon, intestine, kidney, larynx, liver, lung, stomach Reviewed in 1; 53, 54, 55
UGT1A7 Esophagus, orolaryngeal tissue, stomach Reviewed in 1; 54
UGT1A8 Colon, esophagus, intestine, kidney, larynx Reviewed in 1; 54
UGT1A9 Breast, colon, esophagus, liver, kidney, prostate, ovary, skin, testis Reviewed in 1; 54, 56
UGT1A10 Biliary tissue, colon, esophagus, intestine, orolaryngeal tissue, stomach Reviewed in 1 and 6; 54
UGT2A1 Brain, fetal lung, olfactory epithelium 57
UGT2A2 Colon, intestine, liver, stomach 6
UGT2B4 Adipose tissue, adrenals, breast, kidney, liver, lung, ovary, placenta, prostate, skin, testis 42
UGT2B7 Brain, breast, colon, esophagus, intestine, kidney, liver, lung, pancreas 50
UGT2B10 Breast, esophagus, kidney, liver, lung, placenta, prostate, testis 50
UGT2B11 Adipose, adrenal, breast, kidney, liver, lung, prostate, skin 51
UGT2B15 Adipose, breast, esophagus, kidney, liver, lung, ovary, placenta, prostate, skin, testis, uterus 48
UGT2B17 Adrenals, breast, kidney, liver, lung, placenta, skin, ovary, prostate, testis, uterus 52
UGT2B28 Breast, liver 5

 

Glutathione Conjugation Pathway

http://tuberose.com/Liver_Detoxification.html

A primary phase II detoxification route is conjugation with glutathione (a tripeptide composed of three amino acids--cysteine, glutamic acid, and glycine). Glutathione conjugation produces water-soluble mercaptates which are excreted via the kidneys. The elimination of fat-soluble compounds, especially heavy metals like mercury and lead, is dependent upon adequate levels of glutathione, which in turn is dependent upon adequate levels of methionine and cysteine. When increased levels of toxic compounds are present, more methionine is utilized for cysteine and glutathione synthesis. Methionine and cysteine have a protective effect on glutathione and prevent depletion during toxic overload. This, in turn, protects the liver from the damaging effects of toxic compounds and promotes their elimination.

Glutathione is also an important antioxidant. This combination of detoxification and free radical protection, results in glutathione being one of the most important anticarcinogens and antioxidants in our cells, which means that a deficiency is cause of serious liver dysfunction and damage. Exposure to high levels of toxins depletes glutathione faster than it can be produced or absorbed from the diet. This results in increased susceptibility to toxin-induced diseases, such as cancer, especially if phase I detoxification system is highly active. Disease states due to glutathione deficiency are not uncommon

A deficiency can be induced either by diseases that increase the need for glutathione, deficiencies of the nutrients needed for synthesis, or diseases that inhibit its formation. Smoking increases the rate of utilization of glutathione, both in the detoxification of nicotine and in the neutralization of free radicals produced by the toxins in the smoke. Glutathione is available through two routes: diet and synthesis. Dietary glutathione (found in fresh fruits and vegetables, cooked fish, and meat) is absorbed well by the intestines and does not appear to be affected by the digestive processes. Dietary glutathione in foods appears to be efficiently absorbed into the blood. However, the same may not be true for glutathione supplements.

In healthy individuals, a daily dosage of 500 mg of vitamin C may be sufficient to elevate and maintain good tissue glutathione levels. In one double-blind study, the average red blood cell glutathione concentration rose nearly 50% with 500 mg/day of vitamin C. Increasing the dosage to 2,000 mg only raised red blood cell (RBC) glutathione levels by another 5%. Vitamin C raises glutathione by increasing its rate of synthesis. In addition, to vitamin C, other compounds which can help increase glutathione synthesis include N-acetylcysteine (NAC), glycine, and methionine. In an effort to increase antioxidant status in individuals with impaired glutathione synthesis, a variety of antioxidants have been used. Of these agents, only Mega H-, vitamin C and NAC have been able to offer some possible benefit.

Over the past 5-10 years, the use of NAC and glutathione products as antioxidants has become increasingly popular among nutritionally oriented physicians and the public. While supplementing the diet with high doses of NAC may be beneficial in cases of extreme oxidative stress (e.g. AIDS, cancer patients going through chemotherapy, or drug overdose), it may be an unwise practice in healthy individuals.

Genovations - The Great Smokies Diagnostic Laboratory

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.

GSTM1 (1p13.3)
Health Implications
: Glutathione-S-tranferase affords protection against oxidative stress (especially by reducing hydrogen peroxide and by regenerating oxidized vitamins C and E). GST also detoxifies electrophilic compounds including solvents, herbicides, fungicides, polycyclic aromatic hydrocarbons and heavy metals (Mercury, Lead, and Cadmium). Decreased glutathion conjugation capacity may increase toxic burden and increase oxidative stress resulting in a greater risk for various cancers and fatigue syndromes, especially if exposed to toxic compounds.

Minimizing Risks: Regardless of genotype, increasing the body's production of glutathione will reduce oxidative stress and afford greater protection against a wide array of toxins. Numerous supplements can help raise glutathione levels including liberal consumption of colorful vegetables and fruits, vitamin C, n-acetylcysteine and milk thistle. Liberally consume bassica vegetables (broccoli, cauliflower, kale, cabbage, bok choi, etc.) and allium vegetables (onions, garlic, shallots, etc.). Vitamin E supplementation may also be helpful. COnsult your healthcare provider to find the supplement regimen that best fits your overall health needs. If you smoke, stop. Avoid exposure to herbicides, fungicides, insect sprays and industrial solvents.

Amino acid conjugation Pathway

http://tuberose.com/Liver_Detoxification.html

Several amino acids (glyucine, taurine, glutamine, arginine, and ornithine) are used to combine with and neutralize toxins. Of these, glycine is the most commonly utilized in phase II amino acid detoxification. Patients suffering from hepatitis, alcoholic liver disorders, carcinomas, chronic arthritis, hypothyroidism, toxemia of pregnancy, and excessive chemical exposure are commonly found to have a poorly functioning amino acid conjugation system. For example, using the benzoate clearance test (a measure of the rate at which the body detoxifies benzoate by conjugating it with glycine to form hippuric acid, which is excreted by the kidneys), the rate of clearance in those with liver disease is 50% of that in healthy adults

Even in apparently normal adults, a wide variation exists in the activity of the glycine conjugation pathway. This is due no only to genetic variation, but also to the availability of glycine in the liver. Glycine, and the other amino acids used for conjugation, become deficient on a low-protein diet and when chronic exposure to toxins results in depletion.

Methylation Pathway

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Methylation involves conjugating methyl groups to toxins. 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), supporting the use of methionine in conditions of estrogen excess, such as PMS. Its effects in preventing estrogen-induced cholestasis (stagnation of bile in the gall bladder) have been demonstrated in pregnant women and those on oral contraceptives. In addition to its role in promoting estrogen excretion, methionine has been shown to increase the membrane fluidity that is typically decreased by estrogens, thereby restoring several factors that promote bile flow. Methionine also promotes the flow of lipids to and from the liver in humans. Methionine is a major source of numerous sulfur-containing compounds, including the amino acids cysteine and taurine.

Genovations - The Great Smokies Diagnostic Laboratory

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

COMT (V158M)
Health Implications: Catechol-O-methyltransferase inactivates catecholamines, catechol estrogens, and catechol drugs such as L-DOPA. A polymorphism in COMT results in reduced COMT activity, thus decreased degradation of these compounds. Risk may be increased for some neuropsychiatric disorders, imparied estrogen metabolism, increased sensitivity to pain, and late-onset alcoholism.

Minimizing Risks: Avoid excessive alcohol consumption; seek help if alcohol consumption is a health issue. Minimize sustained mental and environmental stress (stress hormones require COMT for their degradation, thus can decrease the methylation of estrogen compounds). Ensure adequate intake of B vitamins, magnesium, and protein.

Note: Epinephrine is the same as adrenaline, and norepinephrine is the same as noradrenaline.

Sulfation Pathway

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Sulfation is the conjugation of toxins with sulfur-containing compounds. The sulfation system is important for detoxifying several drugs, food additives, and, especially, toxins from intestinal bacteria and the environment. In addition to environmental toxins, sulfation is also used to detoxify some normal body chemicals and is the main pathway for the elimination of steroid and thyroid hormones. Since sulfation is also the primary route for the elimination of neurotransmitters, dysfunction in this system may contribute to the development of some nervous system disorders.

Many factors influence the activity of sulfate conjugation. For example, a diet low in methionine and cysteine has been shown to reduce sulfation. Sulfation is also reduced by excessive levels of molybdenum or vitamin B6 (over about 100 mg/day). In some cases, sulfation can be increased by supplemental sulfate, extra amounts of sulfur-containing foods in the diet, and the amino acids taurine and glutathione.

http://www.liverdoctor.com/03_detoxpathways.asp

Neurotransmitters, steroid hormones, certain drugs such as Acetaminophen (also known as paracetamol) ,and many xenobiotic and phenolic compounds.

Me:

And the polymorphism - the first one - that affects disposal of ephinephrine (adrenaline), norepiniephrine (noradrenaline), and dopamine. That struck true with me. When I get mad I have a hard time calming down. And... wow. My own personal research and experience with dopamine reveals that it deals with the attention-switching threshold. I often find myself obsessing in certain projects or games, and hard to shift out. If my liver cant dispose of those chemicals, that would explain that as well. Good lord that's a match.

Acetylation Pathway

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Conjugation of toxins with acetyl-CoA is the primary method by which the body eliminates sulfa drugs. This system appears to be especially sensitive to genetic variation, with those having a poor acetylation system being far more susceptible to sulfa drugs and other antibiotics. While not much is known about how to directly improve the activity of this system, it is known that acetylation is dependent on thiamine, pantothenic acid, and vitamin C.

Genovations - The Great Smokies Diagnostic Laboratory

N-acetyl Transferase detoxifies many environmental toxins, including tobacco smoke and exhaust fumes. Polymorphisms can result in slower than normal or faster than normal addition of an acetyl group to these toxins. Slow acetylators have a build up of toxins in the system and rapid acetylators add acetyl groups so rapidly that they make mistakes in the process. Both slow and rapid acetylators are at increased risk for toxic overload if they are exposed to environmental toxins. If the toxin exposure is reduced, the risk is reduced.

NAT2 (I114T & K268R)
Health Implications
: N-acetyltransferase 1 is found in extra-hepatic tissues, while NAT2 is found predominantly in the liver and the gut. Both are used in the Phase II acetylation of numerous environmental toxins, including heterocyclic aromatic amines. Slow acetyleators do not clear toxins well and the resulting increased total toxic burden can increase the risk of lung, colon, breast, bladder, and head and neck cancers, though results have not been consistent in all studies. Urinary bladder cancer appears to have the most consistent association with low acetyleation.

Minimizing Risks: If you smoke, stop. Your risk of lung cancer is substantially higher than someone with normal NAT activity. Even occasional smoking or exposure to second hand smoke is harmful. Liberal consumption of most vegetables and fruits but especially cruciferous vegetables (broccoli, Brussels sprouts, cauliflower, watercress, and cabbage), garlic, onions, soy, grapes and berries will increase Phase II efficienty, including acetylation.

Glycination Pathway

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Salicylates and benzoate are detoxified primarily through glycination. Benzoate is present in many food substances and is widely used as a food preservative. Many other substances are detoxified as well via the glycine conjugation pathway. Patients suffering from xenobiotic overloads and environmental toxicity may not have sufficient amounts of glycine to cope with the amount of toxins they are carrying.


 

Imbalances in Phases I and II

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Another potential problem occurs because the toxins transformed into activated intermediates by phase I are substantially more reactive. Unless quickly removed from the body by phase II detoxification mechanisms, they can cause widespread problems, especially carcinogenesis. Therefore, the rate at which phase I produces activated intermediates must be balanced by the rate at which phase II finishes their processing. 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.

An imbalance between phase I and phase II can also occur when a person is exposed to large amounts of toxins or exposed to toxins for a long period of time. In these situations, the critical nutrients needed for phase II detoxification are depleted, which allows the highly toxic activated intermediates to build up.

http://www.lef.org/protocols/prtcl-143a.shtml

Ideally, Phase I and Phase II detoxification mechanisms work synergistically. If Phase I detoxification is highly active and Phase II detoxification is lethargic, the individual is referred to as a "pathological detoxifier," a condition which increases sensitivities to environmental poisons.

 

Toxic Overload

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If the phase one and two detoxification pathways become overloaded, there will be a build up of toxins in the body. Many of these toxins are fat soluble and incorporate themselves into fatty parts of the body where they may stay for years, if not for a lifetime. The brain and the endocrine (hormonal) glands are fatty organs, and are common sites for fat-soluble toxins to accumulate. This may result in symptoms of brain dysfunction and hormonal imbalances, such as infertility, breast pain, menstrual disturbances, adrenal gland exhaustion and early menopause. Many of these chemicals (eg. pesticides, petrochemicals) are carcinogenic and have been implicated in the rising incidence of many cancers.