preface
This article describes how all kinds of substances are actively broken down in the intestinal epithelium. In part, this is a protective mechanism against an external toxic load. In addition, many body's own substances and bacterial products that are broken down by the epithelial cells of the small and large intestine. These substances are the source of internal toxic load. Gut epithelial cells contain the same poison-degrading enzymes as the liver. If the intestine and liver enzymes do not function properly and the toxic load is too great, the body does not lose the degradation products sufficiently. Different tissues then become irritated, which can cause chronic diseases, fatigue and eventually cancer. Detoxification by means of food and dietary supplements ensures that the various enzymes in the intestine and liver can function well and matched.
How does the intestine deal with toxic substances?
Man has always had to deal with toxic substances: substances that have been formed by the breakdown of steroids and bacteria, poisonous food, such as berries, plants and mushrooms and poison from animals, such as snakes and insects. The body has an extensive detoxification system. It can be found in the liver, the intestine and the kidneys. The skin and lungs also contain detoxifying enzymes. Today, hundreds of thousands of toxic chemicals extyra are in circulation. We receive these substances through air, drinking water, food, cleaning products, cosmetics and medicines. It is interesting that the 'old'
detoxification system can recognize these chemicals as poison and inactivate them.
The epithelium of the gut is one of the fastest growing tissues in the body. The epithelium contains undifferentiated cells, crypt cells, at the base of a protrusion or villus. These cells grow to the top of the villus in six days. They differentiate during this move. Each differentiated epithelial cell of the small intestine (enterocyte) contains 3,000 microvilli. Together, these microvilli form the so-called brush border in which thousands of receptors can bind food components, bacteria, hormones and many enzymes. The enterocyte has many different functions, including protecting the body against toxins. Intestinal epithelial cells contain enzymes that can degrade toxic substances (5). Toxic substances and their intermediates are absorbed into the blood and transported via the portal vein to the liver for further detoxification. They will eventually end up in the intestine via the bile or be excreted by the kidney.
Protection
The intestinal epithelium has a number of protective mechanisms:
1. The first protection is formed by a mucus layer consisting of a glycocalyx in which 'bound' water (2). Only water-soluble toxic substances can pass through this layer and the carbohydrates in the mucus bind bacteria. The mucus also contains a lot of sulfur, making it resistant to degradation by bacteria (28).
2. Prostaglandins stimulate the production and excretion of mucus and thus play a role in the repair of the mucous membrane (3). Analgesics, NSAIDs such as paracetamol and diclofenac, inhibit the production of these prostaglandins and thereby contribute to damage to the mucous membrane.
3. The peristalsis of the intestine keeps toxic substances moving and accelerates the intestine.
4. Enzymes in the brush border break down toxic substances before they can enter the cell. The hypothalamus, thyroid, pituitary and adrenal glands play a role in regulating these enzymes. Stress reduces enzyme production.
5. The cell membrane of the intestinal cells has a fatty character, which prevents water-soluble substances from being stopped. This means that all substances that can pass through the cell membrane must in one way or another be both fat and water-soluble. Only weak bases and acids are capable of this.
6. An anti-porter system in brush-border cells - a membrane protein with a 'pump' function - can learn to recognize toxic substances and medicines and remove them from cells. This activity is programmed by a special gene (ref?) And it is the reason that medicines sometimes lose their efficacy after a certain period. Based on this principle, cancer cells can become resistant to chemotherapy (ref?).
7. "Good" gut bacteria can also break down medicines and toxic substances. They contain cytochrome P450 and conjugation enzymes. These are discussed in detail below.
8. IgA inhibits the growth of wrong bacteria.
9. Special receptors can bind pathogenic bacteria.
Substances that have been implanted in these barriers end up in the intestinal cells where they are partially broken down before they can enter the bloodstream. Also toxic substances are first processed by enzymes. As we know, the liver is the most important detoxification agent
Microsomes in the enterocyte contain, in addition to cytochrome P450, other enzymes that are essential in detoxification: cytochrome P450-dependent mono-oxygenase enzymes. They can break down many different toxic and carcinogenic substances (18).
If the detoxification activity is too low, eg due to too low CYP or P450 levels, too many toxic substances can pass through the intestine and circulate in the body. Substances formed by intestinal bacteria, lipopolysaccharides (LPS), inhibit CYP activity of the liver. Some drugs can also suppress CYP activity. For example, Prozac reduces the activity of CYP2D6 (ref?). Toxic reactions can occur if combined with other antidepressants that use the same CYP.
1. Iron and selenium deficiency affect cytochromes and thus detoxification. The core of the heamgroup of cytochromes contains iron. In the event of iron deficiency, the cytochrome P450 value decreases strongly. Selenium deficiency also reduces enzyme activity, but less than iron deficiency.
2. Lack of folic acid in the diet already shows a clear reduction of drug metabolism (decrease of 78%) and a reduction of 46% of the heam in intestinal cells after three weeks.
Through the food we get chemical substances inside, such as pesticides, dyes, fungal inhibitors, chemical waste products via drinking water etc. Also substances that we breathe come into circulation. In addition, food itself also contains products that need to be processed and many people use alcohol, cigarettes, medicines or smoked foods. As a result, the enzyme systems of phase I are interrogated, resulting in a chronic increase in cytochrome P450 activity. To give an example: people who smoke cigarettes have an increase in CYP activity. Nicotine is partly converted by CYP into the by-product cotinine. Together with the nicotine, this substance influences steroid metabolism. The DHEA and testosterone production is thereby inhibited. In women who smoke, the estrogen value in the serum is also lower than in non-smoking women. They therefore have a higher risk of osteoporosis. Although the enzymes of phase I are elevated, phase II remains normal or is delayed. The toxic intermediates can not then be caught away in time. The balance between phases I and II will be discussed.
The shortest path of detoxification is in many cases to separate the toxic substance into the lumen of the intestine. This is done by the aforementioned anti-porter pump. This pump is connected to CYP3A4. Many degradation products can therefore be found in the feces.
Phase II
Phase II consists of many enzymes. As in phase I, different enzymes belong to certain substances. There are many different enzymes, because every substance or drug has its own specific CYP and associated conjugation enzyme. Within the intestinal cell, substances that lend themselves to it and degradation products from phase I are bound to metabolites such as glycine, ornithine, acetic acid (acetyl-conjugate), glucose (glucoside conjugate), glucuronic acid, glutathione or sulphate. The enzymes needed for binding of the last three are: uridine diphosphate or UDP glucuronosyl transferase, sulfotransferase and glutathione S transferase. These will then be discussed.
UDP-glucuronosyltransferases
UDP-glucuronosyltransferases or UGTs bind glucuronic acid to various substances. UGT has as a substrate: medicines, for example paracetamol, bile salts, andosterone and testosterone (7). Glucuronic acid conjugation not only has a function in the binding of toxic substances, but also plays a role in the absorption of desirable substances. Genistein, a tumor-inhibiting substance present in soy products, is bound to glucuronic acid and easily absorbed into the intestine (10). UDP-glucuronosyltransferases are possible in higher concentrations present in the intestine than in the liver. With temporary reduction of detoxification in the liver, these intestinal enzymes take over the function of the liver. After removal of part of the liver, an increase of 50% UGTs occurred in the small intestine (8). Vitamin C deficiency reduces the effect of UGTs by 68% (30). Binding to glucuronic acid often appears to be the first step in detoxification. Conjugated substances can be directly excreted by the kidney. When conjugated substances enter the bile via the liver, they reappear in the intestine (31). This may also have disadvantages, since intestinal bacteria produce enzymes (beta-glucuronidase) that can break down the glucuron compound, causing the toxic substances to be released in the intestine (32). This happens, for example, with the toxic substances that are created during roasting of meat. The dark crust of roasted meat contains a substance that is first activated by CYP and then bound to glucuronic acid and then returns to the intestine via the bile. When bacteria break down this substance, a strong cancer develops
In case of a (congenital) deficiency of the UDP-glucuronosyltransferase, an increased serum bilirubin level arises because it can not be converted into bile salt by conjugation. This leads to yellowing of skin or eye-white. This phenomenon is called Gilbert's syndrome and it occurs in 5 to 7% of the population. People with a moderate enzyme deficiency do not suffer much at first sight. However, medicines such as paracetamol are conjugated to a lesser extent, which means that they are more at risk of a burden with toxic substances from the environment and the use of medicines (40).
There are different types of enzymes that depend on glutathione. Glutathione is primarily the main defender against free radicals and is present in every cell of the body. The enzyme that is required for this is called peroxidase.
Glutathione is also involved in the elimination of toxic substances by the enzymes glutathione transferases. These enzymes are present as detoxification enzymes in the liver and intestine. The concentration in the intestine is 60% of that of the liver and these enzymes also increase strongly when a part of the liver is removed (22). Different factors from the diet influence their activity. For example, glutathione S-transferase was twice as high in a group of rats that received oats compared to the group on wheat bran (27). At the University of Nijmegen a lot of research has been done into the increasing effect of Brussels sprouts on glutathione-S-transferase (11). Broccoli also has this effect. The activity of these enzymes decreases as people age (13).
Glutathione is made up of cysteine, glycine and glutamine. Selenium is required during production. Lack of cysteine or glutamine limits glutathione formation. Zinc stimulates the glutathione content, while lipopolysaccharides and heavy metals such as cadmium reduce the content. The use of glutathione supplements makes sense. It is absorbed by the intestinal mucosa and not broken down by enzymes in the intestine. However, the limitation is that it is not included in the mitochondria as it can not pass through their membrane. The glutathione binding to toxic substances, however, takes place outside the mitochondria in the cytoplasm. Glycine itself can also be bound to toxic substances. But when not enough glycine is present, not only the detoxifying capacity, but also the production of glutathione decreases. Glycine is necessary for coenzyme A production and is dependent on vitamin B5.
We can conclude from this that glutathione formation and the activity of the enzyme depends on many factors. Due to a lack of one or more factors, there is a shortage of glutathione, resulting in oxidative stress and a decrease in the detoxifying capacity of the intestine and liver. Glutathione plays an important role in the conjugation of steroids and thyroid hormone. Estrogen breakdown products are carcinogenic. We can get an impression of the glutathione content of the body by determining the reduced glutathione content and the enzyme content of blood.
Sulfonic acid conjugation (Ivonne, I still have to check this out, I do not think the right terms are used here) Sulfer is in any case wrong, is English?)
Certain substances are bound to sulfer under the influence of the enzyme sulphotransferase (SULT). Here too we do not have to deal with 1 enzyme, but countless enzymes that are linked to their specific cytochromes. For example, we find SULT1E2 in higher concentration in women and SULT1A1 in men.
Sulphate is supplied by food such as eggs and dairy products and by cysteine. People who are sensitive to sulphite in sulfurized fruit or wine may have a reduced ability for sulphate conjugation.
Sulfotransferase is necessary for the breakdown of steroid hormones and bacterial products. Neurotransmitters, such as dopamine, are made inactive by sulfur conjugation. DHEA and thyroid hormones T3 and T4 are also bound to sulfer. They can then no longer bind to a receptor. This process can be reversed if necessary. The contraceptive pill is 50% inactivated by sulfer binding in the intestine (29). In the liver, the sulfotransferase is the most important enzyme in the processing of estrogens. The rate of sulfer conjugation depends on the serum concentration of sulfer.
Sulphate-reducing bacteria are present in the intestine and form sulphide. Sulfide is not desirable because it breaks down the main food source, butyrates, of the lining of the large intestine. Methylation enzymes protect the epithelium by binding the sulfides. Butyrates play an important role in the gut, not only as a food source, but also as genetic information in a positive way to influence and thereby reduce inflammation phenomena.
PCP inhibits sulphate conjugation. Also a tevee
Braking phase I
In order to slow down a phase I that is too fast, we can use grapefruit. Researchers indicate that grapefruit juice contains flavonoids (such as naringenin) and coumarins (such as bergamottine) (17). Experimentally, they appear to inhibit P450 3A4 (15). Bailey claims that these substances are active in laboratory tests (16), but that neither of them is the active ingredient. Whatever the case, regular medicine uses grapefruit juice because it slows phase I. As a result, a (toxic) 'medicine' can pass through the intestine more easily, without being broken down by this specific enzyme (15). For example, 5 mg of diazepam produces blood levels that are 3 times higher when taken with a glass of grapefruit juice.
food
In natural medicine too grapefruit and the skin of red grapes are used. Not to work medication in, but to slow phase I and to bring phase I and II into balance with each other. Before using grapefruit juice, one has to ask yourself whether it is desirable to slow phase I. Phase I may have started to work too hard due to extra stress on
harmful substances from food. These substances can then enter the body unhindered and make the patient even more ill. In other words, when eating breakfast bacon or eating a ready breakfast with dyes and coffee and drinking grapefruit juice, these harmful substances are not slowed down. Only if you eat very healthy can grapefruit juice be drunk. It is better to use food that contains no toxic substances and so to bring phase I to rest. Also in the Dutch Journal of Medicine is warned for grapefruit juice, because some medicines can cause symptoms when taken with grapefruit juice (26).
To stimulate the detoxification system, all irritants must be removed from the diet. We must therefore not only slow down phase I, but especially stimulate phase II. One can achieve this by using the right food. Garlic, soybeans and rosemary increase phase II. Cabbages promote the absorption and production of glutathione. The glutathione content of the small intestinal epithelium is 0.49 mg per gram of intestinal tissue. When the food contains 10% cabbage, this increases to 0.63mg / g. With a feed with 40% carbon, glutathione content (21) doubles. The glutathione content in the liver is therefore not increased. Brussels sprouts and broccoli increase the activity of glutathione S-transferase (11). Dietary supplements play an important role in the stimulation of phase II. N-acetyl-cysteine, NAC, supplements the glutathione supply of the cell (23). A deficiency of vitamin A stimulates phase I and lowers the UPD glucuronyl transferase. Vitamin A supplementation restores the balance (17). The use of red wine is doubtful, because chronic alcohol consumption is not recommended. However, red grapes do contain elagic acid, a substance that slows phase I and stimulates phase II (14) and flavonoids that inactivate CYP3A4.
Factors that play a role
The detoxifying capacity of the intestine depends on many factors:
1.Energy production
All cell processes cost energy. Energy (ATP) is produced within the mitochondria. The oxygen required for this is transferred by cytochromes. These are not the same as the P450 cytochromes and also contain iron. Iron deficiency influences energy transfer. Lack of antioxidants and oxidative stress causes damage to the cell and mitochondria and reduction of energy production. Phase I and II enzymes are connected to energy production. The detoxification capacity decreases during oxidative stress.
2. Blood flow
Oxygen deficiency due to reduced blood flow causes serious problems, such as oxidative stress and reduced ATP production and a
reduced intestinal barrier. This causes bacteria and toxins a huge load in the body and damage to organs. Heart patients can become nauseous and become constipated due to inadequate blood flow. This was already noticed by Hippocrates. Heart medications also affect the intestine (20). When the oxygen supply in the intestine decreases, the glutathione-dependent enzymes also decrease. Malondialdehyde appears in the urine, which is a measure of oxidative stress (19).
The enterocyte absorbs nutrients and passes this on to the body. Some of the nutrients are used to build up the intestine itself. Nutritional deficiencies reduce the function of the enterocyte.
Proteins are broken down by pancreatic enzymes. This creates small peptides. These are hydrolyzed by peptidase in the brush border. The enterocyte can most easily include a pettidide of 2 or 3 amino acids. Because the epithelium of the gut grows rapidly, many amino acids are needed
