OUR NATURAL DETOXIFICATION

We are exposed to a great number of xenobiotics (foreign compounds) during the course of our lifetime, including a variety of pharmaceuticals and food components. Many of these show little relationship to previously encountered chemicals or metabolites, and yet we are capable of managing environmental exposure by detoxifying them. To accomplish this task, our bodies have evolved a complex operation of detoxification enzymes. But in our toxic world these systems need help. The enzyme systems generally functioned adequately in the past to minimize the potential of damage from xenobiotics, but in our modern civilization, we are being overwhelmed by them. There is an association between impaired detoxification and illness, such as cancer, neurological disease, fibromyalgia, and chronic fatigue/immune dysfunction syndrome. Therefore, an individual's ability to remove toxins from the body plays a role in the cause or exacerbation of chronic conditions and new diseases. Natural helpers include the sulfuaranes found in crucifer vegetables such as Broccoli and the very best, Broccoli Sprouts. 


The following may be difficult to follow and without some education previously into biochemistry, skip to the last paragraph. Our detoxification systems are highly complex and show a great amount of individual variability. These are extremely responsive to a person’s environment, lifestyle, and genetic uniqueness. The liver is the principal organ of detoxification, although all tissue has some ability to metabolize foreign chemicals. The liver is the largest organ, and is the first body part perfused by chemicals absorbed in the gut. Also there are very high concentrations of most metabolizing enzyme systems relative to other tissues. When food or a drug is taken into the GI tract, it is taken apart in the gut. When it is absorbed into our body, it first enters the hepatic (liver) circulation through the portal vein. Here it is metabolized if possible before it can go into the rest of us, and eventually back to the liver again and again. This is the first pass effect. When the altered substance is fat soluble, it is excreted into the bile, then discharged into our intestine only to be reabsorbed again. This process is repeated many times. Therefore, the term, enterohepatic circulation.

Factors that affect the detoxification are age, individual variation (polymorphism), enterohepatic circulation, nutrition, intestinal flora, gender and drugs that person may be taking. Other sites of chemical metabolism/excretion include the gastrointestinal tract, lungs (volatile compounds), kidneys (water soluble molecules), and the skin (both lipid and water soluble chemicals). These sites at times could have localized toxicity reactions. The detoxification systems are complex. They are divided into three interacting parts or phases each of which can engage with itself or any of the other two to work in harmony defending our body from being acutely or slowly poisoned to death. At times it is overwhelmed and we rapidly or slowly die.

The three parts are termed Phases (I, II, and III) of Detoxication. Variation of activities of these can mean the difference between disease (drug adversity, cancer, arthritis, cardiovascular etc.) and health. To add to the complexity, the Phase System is orchestrated by our genetically endowed CYP 450 enzymes that steer or tune them (for better or for worse). The initial P450-mediated oxidation/Phase I metabolism if possible makes the ingested chemicals water soluble to later be eliminated by the kidney. The subsequent joining of the molecule with a lipid- conjugation is "Phase II" and is eliminated through the bile and eventually into our fecal stream. The newly discovered Phase III gets rid of the offending chemical by importing into a cell then exporting out into a storage or excretion system.

The major Cytochrome (CYP) P450 enzymes involved in metabolism of drugs or exogenous toxins are the CYP3A4, CYP1A1, CYP1A2, CYP2D6, and the CYP2C enzymes. The amount of each of these enzymes present in the liver reflects their importance in endogenous metabolites (hormones etc) and drug metabolism. The'CYP's is a host of enzymes that use iron to oxidize organic molecules, as part of the body's plan to dispose of potentially harmful substances by making them more water-soluble. Adding a hydroxyl group to a xenobiotic is the body's strategy to get rid of the 'drug' and is often followed by joining them to other molecular groups such as glucuronide to increase the solubility even further.

Most of the CYP in man is found in the liver, the main organ involved in drug and toxin removal, but a fair amount is also in the small intestine. CYP usually is found in the 'microsomal' part of the cytoplasm (endoplasmic reticulum). Metabolic clearance of drugs is not the only function of CYP. Recently, it has been found that CYP is involved in vascular autoregulation, particularly in the brain. CYP is involved in the formation of cholesterol, steroids and arachidonic acid metabolites. More on CYP later but let me amplify what I said above.

The Phase I System: The Phase I detoxification system, influenced by the cytochrome P450 supergene family of enzymes, noted above, is generally the first enzymatic defense against foreign compounds. They are nonsynthetic reactions involving oxidation, reduction, hydrolysis, cyclization, and decyclization. Most of our unwanted (detrimental) metabolites and pharmaceuticals are metabolized through these Phase I biotransformation of which is then excreted. At times reactive molecules, which sometimes may be more toxic than the parent molecule, are produced. If these reactive molecules are not further metabolized by Phase II conjugation, they cause damage to proteins, RNA, and DNA within the cell. 



The Phase II System: Phase II are conjugation reactions which generally follow Phase I activation, resulting in a xenobiotic that has been transformed into a fat-soluble compound that can be excreted through the bile. There are at least four types of conjugation reactions present in the body (glucuronidation, sulfation, glutathione and amino acid), These reactions require cofactors such as minerals and micronutrients which must be replenished through dietary sources.

 

Phase III System: Recently, antiporter activity has been defined as the Phase III detoxification system. It is an exchanger or counter-transporter on a membrane protein which is involved in active transport of two or more different molecules or ions across a phospholipid membrane in opposite directions. To make it even more complex there is a secondary active transport, one species of solute moves along its electrochemical gradient, allowing a different species to move against its own electrochemical gradient. This is in contrast to primary active transport, in which all solutes are moved against their concentration gradients, fueled by ATP. The antiporter is an energy-dependent efflux pump, which pumps chemical in question out of a cell, thereby decreasing the intracellular concentration of xenobiotics. Antiporter activity in the intestine appears to be co-regulated with intestinal Phase I Cyp enzymes. An example of the “porter” system is Iodide being actively transported into the thyroid.

Cytochrome P 450: Cytochrome P450 enzymes are present in most tissues of the body, and play important roles in hormone synthesis and breakdown (including estrogen and testosterone synthesis and metabolism), cholesterol synthesis, and vitamin D metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, including food chemicals, drugs and products of our natural molecules such as bilirubin, principally in the liver but so in our intestine. The Human Genome Project has identified 57 human genes coding for the various cytochrome P450 enzyme

These cytochrome proteins are located either in the inner membrane of mitochondria of our cells. CYPs metabolize thousands of internal and exogenous (food and drugs) chemicals. Some CYPs metabolize only one (or a very few), such as CYP19 (aromatase-turns testosterone to estrogen), while others may metabolize multiple substances. The CYPs are the major enzymes involved in drug metabolism, accounting for about 75% of them. Most drugs undergo deactivation by CYPs, either directly or by assisting excretion from the body. As noted, many substances are bioactivated or inactivated by CYPs. Drugs can also increase or decrease the activity of various CYP isozymes either by inducing the biosynthesis of an enzyme or by directly inhibiting the activity of one. This is a major source of adverse drug interactions, since changes in CYP enzyme activity may affect the metabolism and clearance of various of these chemicals. Naturally occurring compounds may also induce or inhibit CYP activity. For example, a bioactive compound (narragin) found in grapefruit juice inhibits CYP3A4-mediated metabolism of statins and calcium blocking antihypertensives, leading to the possibility of overdosing.

So if we cannot keep all the poisons out of our bodies, let us at least aid ourselves with helpers such as the natural inducers of the CYP detoxifiers like the crucifers or the active ingredients in them such as DIM or I3C. It will keep us more out of harm's way if we eat and drink to avoid the known toxins in our food and beverages.