In my last blog, I introduced the liver as – “Our Great Alchemist”. We saw that just like an alchemist, the liver is always hard at work in the shadows, accomplishing many tasks at a time. One of these major tasks is that of detoxification. We would like to concentrate on this task in more detail in this blog. There are two major phases of detoxification in the liver. Some would even argue that there is a third phase that we will touch on here also.
This blog is a bit nerdy, but you can make your way through it. It helps us understand how there are different gears to our liver and which gear you are in, will determine what you detoxify. The first ‘gear’ of course is phase I and the second gear is phase II. So put on your big shoes because we are going to be a bit biochemical in the first few paragraphs.
Phase I detoxification
The most important Phase I reactions are performed by a family of 50 – 100 related enzymes called the cytochrome P450 system (cyt P450), involving either oxidation, reduction or hydrolysis. These enzymes have a specific affinity for differing substrates, responsible for initiating the process of detoxification of exogenous (produced outside the body) compounds such as hydrocarbons and drugs, as well as endogenous (made in the body) compounds such as steroid hormones or other end-products of metabolism that would be toxic if they were allowed to accumulate. Phase I reactions tend to make a compound more polar, and therefore water-soluble. In many cases the detoxified compound is directly eliminated after the Phase I reaction. Phase I reactions can also involve adding or exposing a functional group to a toxic molecule, which in most cases allows the molecule to undergo Phase II detoxification. More complex, especially synthetic man-made substances need intermediary chemicals to be further detoxified in Phase II.
It is important to note that the inducement of the cyt P450 system often involves the generation of free-radicals and reactive oxygen species, which if not properly deactivated in Phase II reactions, can cause tissue damage. An adequate supply of key antioxidants and free radical quenches is therefore essential to prevent tissue damage. Reduced glutathione, superoxide dismutase and additional nutrients such as beta carotene, vitamin C, vitamin E, selenium and N-acetylcysteine act as antioxidants. Other nutrient cofactors required for cytochrome P450 reactions include riboflavin, niacin, magnesium, iron, copper, zinc and certain phytonutrients such as indoles from cruciferous vegetables and quercetin, all of which have been shown to support Phase I detoxification.
Intermediate metabolites produced in Phase I reactions are usually further transformed by Phase II reactions, transforming potential toxins into easily to eliminate substances that are more or less harmless. The faster and more efficient Phase II reactions are, the less chance there is for the potentially toxic intermediate metabolites generated in Phase I reactions to cause tissue damage. The thing is that phase I is usually many times faster than phase II.
Whereas Phase I reactions are in large part initiated by enzymes in the cyt P450 system, Phase II reactions involve a series of distinctly different reactions in which the intermediate metabolites produced during Phase I reactions are conjugated, involving the addition of a molecule to the intermediate metabolite. This process further increases the water-solubility and reduces the biological activity of the intermediate metabolite, allowing it to be harmlessly excreted in the bile or urine. Phase II reactions consist of glucuronidation, amino acid conjugation, sulfation, glutathione conjugation, acetylation and methylation.
Among the conjugation pathways, glutathione conjugation is the primary method by which intermediate metabolites are dealt with. An increased exposure to toxins as well as a poor dietary supply of glutathione promotes glutathione depletion and thus increased damage from the highly reactive intermediates.
As mentioned, maintaining a balance between Phase I and Phase II reactions are key to inhibiting the generation of free radicals that promote tissue damage. In cases where Phase I reactions are more active than Phase II reactions, the accumulation of reactive intermediate metabolites can lead to tissue damage and disease. This virtual ‘logjam’ of the detoxification process can lead to the establishment of chronic diseases within the body. Patients who are chronically in this state are often referred to as “pathological detoxifiers,” and are highly sensitive to fumes found in paints, perfumes and colognes, often react adversely to various pharmaceutical drugs, and may have a strong reaction to drinking caffeinated beverages.
Phase III detoxification
While phase I and II convert the toxin into a molecule that can be removed from the body, phase III is imperative for its removal from the body. Phase III transporters are present in many tissues including the liver, kidneys, intestine, and brain. These transporters act as a barrier for the entry of xenobiotics as well as a mechanism for moving them and endobiotics (enzymes involved in normal endogenous body metabolism) in and out of the cells.
The transporters in Phase III pump toxins through the cell membrane and out of the cell. In the liver, they move glutathione, sulfate and glucuronide conjugates out of cells and into the bile for elimination. In the kidney, they can remove xenobiotics from the blood so that they can be excreted from the body.
Phase III can be supported by different methods. Dietary factors such as adequate fiber to support healthy excretion, as well as adequate clean water to maintain healthy kidney function and urinary excretion. Sweating, in a sauna or through exercise, also helps to remove toxins through the skin. Dietary factors that stimulate the activity of phase III proteins are apple polyphenols (an apple a day will keep the doctor away) and sulforaphane (found in broccoli; yes your mother was right. It is good for you). To increase the amount of energy available to support the function of the phase III transporters, mitochondrial support and different energy producing elements can be incorporated such as thiamin, riboflavin, niacin, pantothenic acid, magnesium, and CoQ10.
Overall, detoxification is important to keep our body in balance in a world of ever-increasing toxins. All phases are crucial, but Phase III is necessary for our bodies to get rid of the toxins.
Even tough we use programs specifically for balancing the liver (yes, I will go into it in much more detail in a future blog), the most common protocol that we have used in the clinic to balance out and regulate these three phases is the 12-day Wild Rose Herbal D-tox.
In the third part of this blog series, we are going to look at assessment of your phase 1 and phase 2 of your liver work.