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Understanding The Detoxification Pathways

In my articles and blog posts I frequently talk about detoxification. It’s quite common for my patients to have followed one or more liver detoxification programs prior to speaking with me for the first time. In fact, I’m sure many people reading this have gone through at least one liver detoxification program over the last few years. And some people have gone through multiple liver detoxifications over the last year alone. However, most people who follow a liver detoxification don’t have a good understanding of the detoxification pathways. As a result, in this post I would like to share some of the basics so that you better understand the different phases of detoxification.

There are two primary phases of detoxification. In the phase one detoxification system, which is known as “biotransformation”, certain toxins are converted into intermediate metabolites which can actually be more harmful than the original compound. In the phase two detoxification system, also known as the conjugation process, these intermediate metabolites are combined with certain molecules and become less toxic and water soluble. And then of course these metabolites are excreted, which is considered as being phase three detoxification. I mentioned how in phase one these toxins can be more harmful, as these intermediate metabolites can cause damage to the proteins, DNA, and RNA if they don’t go through phase two detoxification. As a result, this can be problematic if someone has compromised phase two activity.

What Role Do Cytochromes Play In Detoxification?

Cytochrome P450 enzymes are produced by the liver, and are also found in the kidney, small intestine, lung, adrenals, and most other tissues. They are utilized in phase one. There are 58 different cytochromes, and different cytochromes will play different roles in the metabolism of toxins, which include medications. The cytochrome P450 can be inhibited or induced by certain drugs, as well as by certain nutrients (1) [1]. An inducing agent can increase the rate of another drug’s metabolism, whereas an inhibiting agent can inhibit the drug’s metabolism.

These cytochrome P450 enzymes not only play a role in detoxification, as they are also essential in the metabolism of certain nutrients. For example, the cytochrome P450 enzymes are necessary for the metabolism of vitamin D (2) [2], as well as vitamin E (3) [3]. These cytochromes are also necessary for the metabolism of hormones such as estrogen, as the first step in the metabolism of estrogens is the hydroxylation catalyzed by cytochrome P450 (4) [4].

Genetic Polymorphisms Can Affect Detoxification

Polymorphisms are common genetic defects, and these can occur in the Cytochrome P450 (CYP) family, which in turn can affect the detoxification process. This is especially true with regards to the phase one metabolism of drugs, since almost 80% of drugs are metabolized by these enzymes (5) [5]. For example, if someone has a polymorphism of CYP2D6 then the individual would be considered to be a “poor metabolizer” (5) [5]. And polymorphisms of other CYP genes are also common, such as CYP1A1, 2A6, A13, 2C8, 3A4, and 3A5.

But what’s the significance of these genetic polymorphisms? Simply put, having certain polymorphisms of the CYP enzymes can reduce the person’s ability to detoxify. And some of these polymorphisms have been linked to chronic health conditions. For example, many people with hyperthyroidism and Graves’ Disease will commonly be advised by their endocrinologist to take Propranolol, which is a beta blocker. The cytochrome CYP2D6 is primarily responsible for the metabolism of Propranol (6) [6], along with some other beta blockers, such as metoprolol (7) [7]. As a result, if someone were to have a genetic polymorphism of this cytochrome then this can affect the clearance of Propranol. Why is this important? Well, someone who has a polymorphism of CYP2D6 might require a different dosage of these beta blockers when compared to someone who doesn’t have such a polymorphism. Of course most people aren’t tested for these polymorphisms, and so the medical doctor will just recommend what he or she thinks is the appropriate dosage. In the future more and more people are going to be tested for these genetic polymorphisms, which in turn will impact the drug recommendations given by medical doctors.

But even though the focus of this post is on the detoxification pathways, these polymorphisms can cause other health issues. As I mentioned earlier, people who have a polymorphism of CYP2D6 are considered to be “poor metabolizers”. Well, a few studies have linked this polymorphism with Parkinson’s disease (8) [8] (9) [9]. This doesn’t mean that everyone with this specific polymorphism will develop Parkinson’s, although it very well might make that person more susceptible to developing this condition. There is also evidence that some of these polymorphisms can increase one’s susceptibility to cancer (10) [10].

Although I’ve been focusing on CYP2D6, there are many other types of polymorphisms of the cytochromes one can have, as I briefly listed some of them earlier. In addition to having polymorphisms of the cytochromes, there are other polymorphisms which can affect detoxification. For example, polymorphisms of glutathione S-transferase M1 (GSTM1) can have a negative effect on detoxification. N-Acetyltransferases (NAT) are key enzymes in the conjugation of certain drugs and other xenobiotics with an arylamine structure (11) [11], and these polymorphisms can also affect detoxification.

How Can Nutrient Deficiencies Affect Detoxification?

Having certain nutrient deficiencies can have a negative effect on detoxification. And the reason for this is because nutrients are necessary for the proper functioning of the detoxification pathways. Some of the more important nutrients required for phase one detoxification include vitamins B2, B3, B6, B12, and folate. Many reading this are familiar with glutathione, which is an important antioxidant that also plays an important role in both phase one and phase two detoxification. The amino acids glycine, taurine, glutamine, cysteine, and methionine are all important for phase two detoxification.

However, when looking back at phase one detoxification, remember that intermediary metabolites are produced, and these can lead to the formation of free radicals. As a result, it is important to have sufficient antioxidants to help neutralize these free radical reactions. This not only includes glutathione, but others such as selenium and vitamin C.

The Complexity of The Phase Two Detoxification System

As I briefly mentioned earlier, phase two involves the conjugation of the intermediate metabolite with another molecule to make it less toxic and water soluble. While this might sound easy enough, it actually can be quite complex, as there are numerous pathways required in this phase. This includes acetylation, acylation, sulfur conjugation, methylation, and glucuronic acid conjugation. I’m not going to discuss these here, but just remember that having problems with any one of these pathways can affect phase two detoxification.

But what would cause these systems to malfunction? Well, there can be numerous factors which cause this. Having a genetic defect such as an MTHFR polymorphism can cause problems. Or having a certain nutrient deficiency can also lead to big issues. For example, if someone has a vitamin B5 (pantothenic acid) deficiency then this can affect acetylation. If they have a deficiency in glycine or taurine then this can affect acylation. If they have a deficiency of vitamin A or niacin then this can affect sulfation, etc. So for example, glutathione synthesis is magnesium-dependent. There are other important nutrients and amino acids required, but if someone has a severe magnesium deficiency, yet they take something such as N-acetyl cysteine to help increase glutathione levels, they won’t be able to accomplish this if the magnesium deficiency isn’t addressed.

Thyroid Health and Detoxification

Thyroid hormones play an important role in detoxification. Either a hypothyroid or hyperthyroid state can have a negative effect on the cytochrome P450 enzymes, which you now know play an important role in phase one detoxification. For example, one study in mice showed that hypothyroidism can affect the metabolism of xenobiotics by suppressing the CYP3A enzyme, while inducing the CYP2B enzyme (12) [12]. Numerous studies also show that a thyroid imbalance can affect the cytochrome enzymes (13) [13] (14) [14] (15) [15].

So what does this mean? Well, it means that having hypothyroidism or hyperthyroidism can have a negative effect on detoxification. And so while it’s beneficial for people with these conditions to do things to detoxify their body, if they have a thyroid hormone imbalance then this can reduce the ability of body to metabolize toxins. And so it is important to correct any thyroid hormone imbalance in order to achieve optimal detoxification.

So hopefully you have a better understanding of the importance of the detoxification pathways. When someone undergoes a liver detoxification, the foods and supplements they are taking should support these pathways. If someone is deficient in one of these nutrients then this will have a negative effect on detoxification. However, having certain genetic polymorphisms can also have a negative effect on the detoxification pathways. In addition, having healthy thyroid hormone levels are also important for proper functioning of the detoxification pathways.