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Toxins can enter the body in three ways: by absorption through the skin; by inhalation through the respiratory tract into the lungs; or by ingestion through the mouth into the gastrointestinal tract. The skin, lungs, intestines, and kidneys have all developed some protective mechanisms and methods of detoxification, although the liver is the body’s major organ of detoxification.
The liver is a dome-shaped gland that fits under the diaphragm, just under the right ribcage. It is considered a gland because it secretes bile, and it is the largest gland in the body.
The liver is divided into two major regions, the right and left lobes. The right lobe, which has three smaller lobes, is larger than the left, which has two smaller lobes. Each of the five lobes is composed of compartments called liver lobules.
The central vein passes through the center of each lobule and drains away waste products from the liver. The cells of the lobule closest to the central vein are known as centrilobular hepatocytes (liver cells). Cytochrome P-450 is most highly concentrated in these cells, and detoxification activity is also highest in this area.
On the other side of the liver, the hepatic artery and portal vein are known as the periportal system. The hepatic artery supplies oxygen to the liver directly from the heart and lungs. The cells of the lobule closest to the hepatic artery have the highest concentration of oxygen in the liver. They also have the highest concentration of nutrients because the liver is the first organ to receive nutrients absorbed by the GI tract, delivered by the portal vein. These cells also have the highest exposure to xenobiotics in the liver, as well as higher concentrations of glutathione and transaminase enzymes. The levels of these enzymes are tested in the standard blood chemistry test for liver function.
- HOW TOXINS ENTER THE LIVER
- The liver is situated to receive a majority of the venous blood from the lower body, the kidneys, the spleen, and the gastrointestinal tract. Approximately 1500 ml of blood, containing many different toxins, flows through the liver every minute.
- The liver is the main organ for biotransformation of chemicals. However, it is susceptible to tissue injury from the toxic effects of chemicals, and if it becomes overloaded, can be permanently damaged. Some chemicals are toxic to specific parts of the liver.
- PROTECTIVE DEVICES
- Adequate levels of the conjugation enzymes needed for Phase II are protective for the liver. They help prevent the buildup of toxic substances formed as a result of biotransformation during Phase I of detoxification. The presence of adequate antioxidants to quench free radicals is also protective for the liver.
- Even when 80 percent of the cells of the liver are damaged, the liver can continue to function, but with reduced efficiency. It has the ability to restore and replace these damaged cells, and can recover if the sources of the toxins are removed.
- The bulk of toxic substances are detoxified in the liver. The liver removes chemicals that have been absorbed into the blood, and excretes them into the bile stored in the gallbladder. Both Phase I and Phase II detoxification processes are active in the cells of the liver, and the liver’s cytochrome P-450 system is the body’s first-line site for the detoxification of foreign chemicals.
- Over 300 known chemicals can induce (increase) enzyme system activity in the liver. These chemicals can lead to more enzymes being present and a faster rate of detoxification. They also increase the amount of endoplasmic reticulum (membranes in the cell where detoxification occurs) in the liver.
- While some chemicals increase the liver’s metabolic action, others inhibit the activity of cytochrome P-450 and other detoxification enzymes. Chemicals can cause inhibition in several ways:
- competition between two or more compounds for the same detoxifying enzymes
- inhibition of enzyme synthesis
- inactivation or destruction of enzymes or the endoplasmic reticulum
- overwhelming of the detoxification enzyme systems
- depletion of necessary cofactors for Phase II
- Inhibition of cytochrome P-450 can lead to the buildup of toxins in the body. For example, theophylline is a drug used to control asthma and belongs to the same family as caffeine. It can build up to toxic levels if the patient is given erythromycin simultaneously, which inhibits the cytochrome P-450 enzyme system from breaking down the theophylline. Erythromycin and antifungals such as ketoconazole can also inhibit the breakdown of Seldane, an antihistamine. Because the resulting high levels of Seldane can cause heart rhythm disturbances, it has been taken off the market.
The principal excretory organs in all vertebrates, the kidneys lie in the back of the abdominal wall, one on each side of the backbone. They are bean-shaped, and on the concave side of each one is an area called the hilus, where the renal (kidney) artery enters and the renal vein exits. The adrenal glands sit on top of the kidneys. The kidneys are also regulatory organs, helping to maintain homeostasis (physiological balance between all body organs).
Each of the kidneys consists of the outer cortex and the inner medulla. The cortex receives 85 percent of the total renal blood flow and is composed of nephrons, which are excretory units. Each kidney has over one million nephrons. Each nephron has three parts:
- the vascular or blood circulationcomponent, composed of interconnected capillaries;
- the glomerulus, the filtering tissues of the kidney; and
- the tubules, small tubes or ducts that reabsorb 98 to 99 percent of the salts and water filtered by the glomerulus, for the body’s use. The last tubule, the collecting duct, concentrates the remainder of the fluid as urine.
The nephron’s tubular element joins the ureter, which exits from the same side of the kidney as the renal vein and artery. The ureter carries the urine to the bladder, a balloon-shaped storage chamber. As urine enters the bladder, its walls of smooth muscle unfold to the volume needed to contain the urine. When the bladder becomes distended, receptors are stimulated to contract the bladder. The urine then flows under voluntary control through the urethra, and out of the body.
Kidneys filter out cellular waste, metabolic waste (mostly breakdown products of protein metabolism), drugs, and toxins from the blood. In addition to filtering the blood and draining wastes, the kidneys eliminate foreign chemicals from the body, and regulate the body’s pH balance, calcium metabolism, electrolyte balance, fluid balance, and extra cellular volume (circulating fluid outside the cells). The kidneys produce a hormone that stimulates red blood cell production, helps to regulate blood pressure, and also plays a role in vitamin D metabolism.
- HOW TOXINS ENTER THE KIDNEYS
- The kidneys have an even higher blood flow than the brain, liver, or heart, and receive 25 percent of the body’s total blood volume, causing high exposure to chemicals carried in the blood. They reabsorb and redistribute about 99 percent of the blood volume received, and 0.1 percent of the blood filtered becomes urine.
- PROTECTIVE DEVICES
- An adequate supply of Phase II enzymes is protective for the kidney, as is the intake of adequate fluids. Kidney stones, which can damage the kidneys, can form when there is too little fluid. Accurate pH control of the urine is also protective, as kidney stones tend to form when urine pH is not optimum.
Kidney disease can be quite advanced before it is detected, as the kidneys can lose 80 percent of their function before symptoms appear.
- The kidneys excrete chemicals that have been prepared by Phase II detoxification in other parts of the body. Phase II converts lipid-soluble nonpolar substances into more polar substances. This makes them less fat-soluble and less likely to be reabsorbed by the kidney tubules. They are then available for excretion in the urine.
Some chemicals (for example, ammonia) are secreted by the tubules and move into fluid in the lumen (interior) of the tubule, where they are then eliminated from the body in the urine. Tubule cells are also capable of catabolizing (breaking down) certain organic compounds, which destroys them even though they are not excreted in the urine.
The gastrointestinal (GI) tract includes the mouth, pharynx, esophagus, stomach, small intestine, large intestine, and rectum. The other portion of the gastrointestinal system is made up of glandular organs that secrete substances into the gastrointestinal tract. These glands include the salivary glands, liver, gallbladder, and pancreas. The function of the gastrointestinal system is to process the food we eat into a form that the circulatory system can distribute to the cells of the body.
The GI tract is a tube that runs through the body from the mouth to the anus. In adults, this tube is approximately 15 feet long. The contents of the lumen, which is the interior of this tube, are technically outside the body. For example, millions of bacteria populate the large intestine. Most of them are beneficial, but if these bacteria should leave the intestine and enter the body, they are harmful and can even be lethal.
Food is taken into the mouth where it is mixed with saliva, which moistens and lubricates the food particles so they may be swallowed easily. The saliva contains an enzyme called amylase that aids in digesting carbohydrates.
The pharynx and esophagus serve as a pathway to deliver the food from the mouth to the stomach. The movement of these two parts of the gastrointestinal tract controls the process of swallowing. The stomach mixes the food with hydrochloric acid, pepsin, gastrin, and mucus. The pepsin processes protein, and gastrin stimulates the release of hydrochloric acid. These materials break the food down into even smaller particles, and the resulting mixture is known as chyme. In addition to breaking down the particles of food, the hydrochloric acid also kills almost all the bacteria that enter the body with the food. Some do survive and subsequently begin to live and multiply in the large intestine. The stomach also stores food while it is being partially digested. It then delivers fluid and partially digested food to the small intestine in amounts that allow for maximum digestion and absorption.
The last stages of digestion and absorption take place in the small intestine, which is the longest portion of the digestive tract. Enzymes from the pancreas break down chyme into monosaccharides, fatty acids, and amino acids. These substances then cross the layer of epithelial cells that line the intestinal wall and enter the blood and lymph, the watery fluid in the lymph vessels.
A small volume of water, minerals, and undigested material passes into the large intestine. This material is temporarily stored and acted upon by the intestinal bacteria. The large intestine concentrates the material by removing water. The concentrated material is then eliminated from the body through defecation when the rectum becomes distended. The eliminated material is called feces and consists of a small amount of food that was not digested or absorbed, toxins, cast-off cells, and bacteria, which contribute to the bulk of the feces.
- HOW TOXINS ENTER THE GI TRACT
- Toxins arrive in the stomach after being ingested in food or water, or being breathed in through the nose or mouth and swallowed. The absorption of toxins in the stomach depends on the amount ingested, as well as the degree of lipid or water solubility, degree of ionization, molecular size, and pH of the toxin. Digestive enzymes, hydrochloric acid, and bile acids also affect the absorption and metabolism of toxins.
- The intestines are exposed to bacteria, viruses, yeasts and parasites, food and plant ingredients, and toxins in food, water, and the environment. Foreign chemicals may also be absorbed into the body from the small and large intestines. To be absorbed, chemicals must be made soluble before they come into contact with the intestinal mucosa. Unabsorbed chemicals reach their highest concentration in the colon (large intestine).
Chemicals are usually absorbed slowly from the GI tract, but the amount absorbed depends on how rapidly the chemicals move through it. The faster a chemical passes through, the less is absorbed. The degree of intestinal absorption is also affected by gastric emptying time, intestinal motility, the size and condition of the surface area of the small intestine, blood flow to the intestine, diet, genetic factors, and age.
- PROTECTIVE DEVICES
- The GI tract has various defense mechanisms against bacteria, viruses, yeasts, parasites, and chemical toxins. It is protected by enzymes, mucus, normal intestinal bacteria, intestinal secretions, and the innermost layer of epithelial cells.
- In the intestines, the first barrier to the absorption of chemicals is the unstirred water layer. This layer of immobile fluid coats the intestinal mucosa (mucous membrane). It has a mucus layer and an acid micro layer that is rich in protons (particles with a positive charge). It acts as a barrier to the chemical penetration of the mucosa. Nonpolar, lipid-soluble chemicals diffuse through the unstirred water layer more slowly than they would penetrate a cell membrane. Pesticides, dyes, and food additives are examples of nonpolar chemicals.
The second barrier is gastrointestinal mucus, which protects the intestinal mucosa from physical and chemical injury, and acts as a lubricant. Cells in the esophagus, stomach, small intestine, and large intestine all produce mucus. Mucus consists of 95 percent water, with the remainder made up of salts, proteins, nucleic acids, and mucins. Mucins, composed of carbohydrates, lipids, and proteins, give mucus its viscous, gel-like texture. Mucus is sticky and can trap large molecules, such as metallic chemicals. It can also trap parasites and bacteria, and can bind viruses, helping to eliminate them in the feces.
- The third barrier to absorption of chemicals is the small intestine’s acid microclimate layer, consisting mostly of protons. This layer has a 5.9 pH, which is acidic compared to the 7.3 pH of the lumen of the small intestine, which is mildly alkaline. The acid microclimate layer may influence the permeability of weak acids and alkalis, by repelling acids and neutralizing alkalis.
- The fourth barrier is the concentration of bacteria in the large intestine or colon. More than 400 species of bacteria reside in the colon. Intestinal bacteria metabolize drugs and other chemicals. However, bacteria may metabolize chemicals in a manner completely opposite to the body’s metabolism, restoring a xenobiotic to its original form, allowing it to reenter circulation and again become part of the toxic load.
- Another defense mechanism is the rapid shedding of intestinal cells. They are some of the most actively dividing cells in the body, with up to 100 cells per hour formed in the intestines, and billions of cells shed every day. Metals and lipid-soluble chemicals may be excreted from the intestines along with the old cells.
- Both Phase I and Phase II detoxification systems are found in the GI tract, which is the second major site of detoxification in the body. Phase I changes the chemicals so that Phase II can add a small molecule. The GI tract contains the same biotransformation enzymes as the liver, but metabolism in the GI tract is slower than in the liver. Depending on the composition of the toxin, the GI tract can transform a xenobiotic to either a less toxic chemical or a more toxic chemical.
- In the stomach, pepsin and hydrochloric acid can help break down chemicals and toxins. The intestines contain bile acids and various enzymes, such as proteases, lipases, and glucuronidases, which can also break down chemicals and toxins.
- The mixed-function amine oxidase system is most active in the duodenum, the first part of the small intestine. Mature enterocytes, the cells lining the intestine, contain the largest amount of cytochrome P-450 activity. The activity of these Phase I enzymes decreases from the duodenum to the colon.
- Many factors affect the ability of the intestines to metabolize xenobiotics. For example, when people go on starvation or semi-starvation diets, the activity of many of the metabolic enzymes decreases. Iron deficiency and selenium deficiency can reduce cytochrome P-450 activity. Cruciferous plants (cabbage, cauliflower, broccoli) increase the activity of the mixed-function amine oxidase system. Chemicals can decrease or increase enzyme activity, depending on the type of chemical. Enzyme activity in a portion of the small intestine called the jejunum has been found to be lower in females than in males. The very young and the very old also seem to have less active detoxification enzymes.
- The gut itself can act as an organ of excretion for toxins. Cells lining the intestinal walls can secrete xenobiotics into the intestines. Strong acids and digitalis compounds are secreted from the bloodstream into the intestinal lumen, where they are then excreted in the feces.
The skin consists of two major layers. The outer layer, the epidermis, is made of four thin layers of epithelial cells. The inner layer, the dermis, is composed of connective tissue.
- THE EPIDERMIS
- This outer layer of protective skin is approximately 1 millimetre thick and is composed of tightly packed cells. The top layer of the epidermis is pigmented and varies in thickness in different areas of the body, determining how easily chemicals can penetrate the skin and how rapidly they are absorbed. An exception is the palm of the hand, where this layer is thicker than in other areas of the body, yet absorbs chemicals more readily.
New skin cells form in the basal cell layer, replacing the entire epidermis approximately once a month. Melanocyte cells, which form part of the epidermis, produce melanin pigment. Melanin determines skin color, and also protects against ultraviolet injury, sunburn, and skin cancer. Melanin absorbs ultraviolet and visible light, and quenches free radicals.
- Epidermal cells produce lipids and a protein called keratin. Lipids, which include cholesterol and free fatty acids, help protect the skin against water loss and cracking. With the aid of sunlight, the epidermis also produces vitamin D, an essential nutrient for maintaining calcium and phosphate levels in the body (needed for the growth and repair of bones).
- THE DERMIS
- The thicker dermis lies under the epidermis and is composed of the proteins collagen and elastin. These proteins make the skin elastic and give it strength. Unlike the epidermis, it is well supplied with blood, lymph vessels, and nerves.
- The dermis also contains the eccrine and apocrine sweat glands, sebaceous glands, and hair follicles. Eccrine sweat glands are distributed over the body’s surface, helping to regulate its temperature. Apocrine sweat glands open into hair follicles and lose cells as they release secretions. Sebaceous glands are located near hair follicles. They secrete sebum, a lipid mixture that has some antibacterial and antifungal properties. Sebum also helps the body excrete lipid-soluble toxins, but only in small amounts.
- HOW TOXINS ENTER THE SKIN
- Toxins vary in their ability to enter the skin, and several factors affect their absorption. To be absorbed, a toxin must also be somewhat water-soluble. Toxins that are only lipid-soluble or only water-soluble are poorly absorbed. Oily solutions usually penetrate the skin easily, as it readily absorbs lipids. When the skin is wet, water-soluble chemicals penetrate more easily. At higher environmental temperatures, the skin is more absorbent. In addition, chemicals penetrate cracked or injured skin more easily than intact skin. Some toxins are absorbed directly through hair follicles in the skin.
- Solvents can easily penetrate the skin because of their lipid (fat) solubility. Caustic chemicals, such as acids and alkaline solutions, can also penetrate the skin. Once a chemical has penetrated the epidermis, it moves into the dermis. The rich blood supply of the dermis readily transports the chemical into the bloodstream.
- PROTECTIVE DEVICES
- The normal microbial flora of the skin is a major barrier to infection, as is the sebum. Although sebum helps to prevent the invasion of substances from the external environment, such as bacteria, it cannot block the absorption of toxins through the skin. The epidermal cells are also capable of producing a variety of lipids that afford protection similar to that of sebum, but cannot stop toxins. Hair on the skin can be protective if it prevents a toxic substance from reaching the skin.
- Some people use physical barriers in an attempt to protect against toxic skin exposures. Barrier creams are one method, although they cannot usually block toxin absorption. Rubber gloves may be useful, but some chemicals and microorganisms can penetrate the gloves. Thin plastic gloves prevent toxins from contacting the skin. However, if a chemical gets inside the glove, it will actually be absorbed more readily.
- Because it contains the enzyme cytochrome P-450 the skin can metabolize drugs, steroid hormones, and some xenobiotics. It converts these chemicals into more water-soluble forms, which can then be excreted from the body. Small amounts of toxins are eliminated in the sweat excreted from the pores and through the sebaceous glands of the skin.
The lungs are part of the respiratory tract. The upper air passage of the respiratory tract consists of the nose, the pharynx, the hypo-pharynx, and the larynx, which houses the vocal cords. The lower air passage stretches from the vocal cords through the trachea and into the lungs.
As we breathe, air enters the upper passage, then traverses the trachea. This area is the narrowest cross-section of the entire airway. The trachea branches into the right and left main stem bronchi, or bronchial tubes, behind the ribcage. One bronchi enters each lung. The bronchi then divide into two to three more branches, called bronchioles. The bronchioles lead to air sacs called alveolar sacs or alveoli. Their total surface area is estimated to be 70 square meters.
Oxygen is extracted from the air we breathe into the lungs and supplied to millions of alveoli, which pass oxygen molecules into the capillaries. Oxygen then combines with hemoglobin in the red blood cells and is carried to the rest of the body.
Exhaling diffuses carbon dioxide molecules from the capillaries into the alveoli and expels them from the body through the bronchi, trachea, and upper air passage.
Three diseases affect the bronchial tube system: asthma, bronchitis, and emphysema. Asthma is characterized by attacks of breathing difficulty. Bronchitis is an inflammation of the bronchial tubes. Toxins can trigger both asthma and bronchitis, which are reversible in their early stages. The toxins in cigarette smoke can cause both chronic bronchitis and emphysema. Emphysema destroys lung elasticity by damaging the walls separating the alveoli from one another, creating tiny craters. Other alveoli become permanently enlarged. Emphysema is irreversible.
- HOW TOXINS ENTER THE LUNGS
- The lungs have the greatest exposure of any organ to the environment. The air we breathe contains microorganisms, chemicals, dust, and pollution. Small solid particles and liquid aerosols can easily enter the lungs and be deposited in three ways: impaction, sedimentation, and diffusion. Gases are absorbed directly through the cells lining the respiratory tract.
- In impaction, large particles continue in straight paths through the airway passages. Most larger particles land on the surface of the nose and throat area (nasopharynx) or at the branching of the bronchi. These particles become embedded in mucus or trapped by nasal hairs and are eliminated by sneezing, swallowing, or blowing the nose. The nasopharynx removes 95 percent of particles 5 microns or larger.
- Medium-sized particles, 1 micron (the size of a cell) to 5 microns in diameter, are deposited in the lungs by sedimentation. Most of these land in the mucus layer of the bronchioles, and are eventually either moved up in the mucus and exhaled, or swallowed. If the particles do reach the alveoli, they can become trapped permanently and may damage the lungs.
- The smallest aerosol particles, less than 0.1 micron in diameter, are deposited in the lungs by diffusion. Many of these particles are exhaled immediately, but those that become trapped can eventually cause lung disease, known as pneumoconiosis. Two types of pneumoconiosis are asbestosis, caused by asbestos fibers, and silicosis, caused by silica dust.
- Gases are absorbed differently in the respiratory tract, depending on their solubility and flow rate, and the duration of exposure. Most absorption of gases takes place in the upper air passages. Some gases dissolve in the fluid that lines the epithelium (the cell layer lining the respiratory tract).
The nose absorbs gases more readily when air flow is increased, which may account for increased absorption by physically active people. The gas may also alter the lining fluid, so that the rate of absorption is increased.
- PROTECTIVE DEVICES
- The lungs protect themselves against environmental pollutants with filters, epithelial barriers, enzyme systems, and immune responses. Filters include mucus and cilia.
- Mucus is produced by glands located beneath the epithelium. Certain cells contain cilia, which are hair like projections that beat in a synchronized fashion at about a thousand times per minute. Together, mucus traps particles and cilia help to move them out of the lungs. A person can then sneeze and cough out the irritants. However, cilia cannot transport particles if there is insufficient mucus. Influenza virus can paralyze the cilia, leading to secondary bacterial infections. Some people have a condition known as immotile cilia syndrome, which means their cilia do not move, and they are prone to sinus and respiratory tract infections.
- Epithelial barriers consist of special cells in the epithelium. Alveolar macrophages, a type of white cell, ingest particles, and kill bacteria and viruses, which they then present to lymphocytes. The lymphocytes, another type of white cell, destroy them. Alveolar macrophages also contain aryl hydrocarbon hydroxylase, a type of enzyme that detoxifies chemicals.
- In addition, an enzyme system helps to protect the lungs. When particles are inhaled, inflammatory enzymes, known as proteases, are released. These proteases can damage the lung cells or the connective tissue in the lungs. Specific proteins known as antiproteases protect the alveoli by combining with proteases to inactivate them. Cigarette smoke destroys the balance between proteases and antiproteases, increasing the activity of the proteases. The most common antiprotease is alpha-I-anti-trypsin. People with a deficiency of this antiprotease are more prone to emphysema.
- The lungs contain enzymes from the mixed function oxidase family, enabling them to metabolize drugs and xenobiotics to more water-soluble chemicals, which can then be excreted by the kidneys.
- The lungs also have antioxidant enzymes to counteract free radicals, including superoxide dismutase, glutathione enzymes, and catalase. In addition, alveolar lining fluid, containing transferrin, ceruloplasmin, and glutathione, protects the lungs from oxidant stress. Vitamin E, an antioxidant found in cell membranes, protects the lungs against toxic lipid peroxides produced by the cell membranes of the lungs when attacked by organisms. In patients who smoke cigarettes, the fluid lining the alveloi can be deficient in vitamin E.
- Finally, the lungs have immune responses to protect them against inhaled organisms. Lymphocytes in the lungs produce immunoglobulins (antibodies), while other immunoglobulins cross from the blood into the lungs. Immunoglobulins IgA, IgG, and IgE have all been found in the respiratory tract. IgA neutralizes many viruses, and it seems to prevent antigen absorption across the lung cells. T-lymphocytes (white blood cells that help fight infection) help protect the lungs against microbes and tumor cells. T-lymphocytes also release lymphokines, which are molecules that activate and stimulate macrophages (white blood cells that ingest foreign material).