The liver is the body’s major organ of detoxification. It uses a three step process, known as Phase 1, Phase 2, and Phase 3 detoxification to neutralize toxins. These toxins come from various sources including the air, diet, drugs, alcohol, smoking, as well as metabolic by-products such as hormones and inflammatory by-products. It is therefore not a tremendous leap of faith to realize that lifestyle factors play a significant role in the accumulation of toxins. The build-up of toxins results in cellular damage, and eventually chronic disease.
The two step protective role the liver plays is known as phase 1 and phase 2 detoxification. Each Phase is utilized to convert toxins into a less toxic substance for excretion.
Phase 1 Detoxification
The Phase one detoxification pathway converts a toxic chemical into a less harmful chemical and is achieved by various chemical reactions such as oxidation, reduction and hydrolysis. This biotransformation converts the lipophilic compounds into more water-soluble metabolites which can be efficiently eliminated from the body. During this process free radicals are produced which, if excessive, can damage the liver cells. Phase 1 is catalyzed by the enzymes of the cytochrome P450 group. These enzymes are found in the cells of the liver that are called Hepatocytes.
The Cytochrome P450 pathway is induced by the presence of various chemicals and the production of free radicals, or reactive oxygen species (ROS) is kept in check by antioxidants. However, if these antioxidants, such as C, E and beta-carotenes are lacking, then these free radicals are free to do damage to the body. Therefore, an adequate supply of various antioxidants is necessary to quench these free radicals to prevent tissue damage.
Furthermore, exposures to certain 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 over activity results in high levels of ROS which, if not further metabolised by Phase II conjugation, may cause damage to proteins, RNA, and DNA within the cell.
In addition to inducers of the Cytochrome P450 pathway, there are also those substances that are know to inhibit, such as naringenin found in grapefruit juice. This has the potential to be dangerous as some drugs can be left active in the bloodstream and therefore continuing to exert unwanted effects.
A polymorphism, or genetic variability in the Cytochrome P450 can effect how a toxin is metabolized. The area this can have the greatest effect is upon the metabolism of drugs. It can cause unexpected side effects dependent upon the drug and enzyme involved and also produce a therapeutic failure. Interactions with common drugs such as statins, warfarin, antidepressants and antiepileptic are often associated with the P450 enzymes.
Phase 2 detoxification
Phase 2 detoxification is referred to as conjugation and this is the process of adding a molecule to the xenobiotic to make it hydrophilic and therefore theoretically able to be excreted through the bile or kidneys. The end products of conjugation have increased molecular weight and tend to be less active than the products of phase 1 reactions.
There are six phase 2 detoxification pathways:
Glutathione conjugation
Amino acid conjugation
Acetylation
Methylation
Sulphation
Glucoronidation
These conjugation molecules join with specific enzymes to catalyze the reaction process. The liver is then able to turn drugs, hormones, and other various toxins into substances that are secreted from the body. Any lack of these enzymes or their cofactors will result in the xenobiotic remaining active and therefore potential to cause damage within the body.
Phase 3 Detoxification
Latest research has identified a third detoxification pathway; Phase 3 detoxification. It is thought that through this pathway the now water soluble molecules are excreted. Although a lesser studied pathway, it is essential to the removal of waste. Often referred to as the antiporter pathway, within which more than 350 antiporter proteins have been identified, the best known and most studied is the of which is the the best known and most studied transporter known as P-glycoprotein.
P-glycoprotein is found in the intestinal epithelium where it pumps zenobiotics back into the intestinal epithelium, the liver where it pumps toxins into the bile ducts, and in the proximal tubule of the kidney where it pumps toxins back into the urine-conducting ducts. It can also be found in the blood brain barrier and the blood-testis barrier.
The transporters in Phase III belong to a family of proteins called the ABC transporters, or ATP-binding cassette, as they require ATP, or energy, to pump toxins through the cell membrane and out of the cell. Phase III transporters also decrease the effectiveness of pharmaceutical therapies as they increase their clearance from the body, thus reducing the load on the liver. This is an important note for chemotherapy drugs, as the transporters enable cancer cells to become resistant.
In this day and age of an ever increasing toxic burden around us it is essential to support and maintain good detoxification and a balance through all of the pathways. In order to do this a good understanding of the detoxification processes is required, particularly amongst those in a professional capacity looking to support those who seek advice and treatment.
