This is the second of two blog posts discussing how to optimize detoxification. The reason why I put together these posts is because many people do things to detoxify their liver, but most don’t have a good understanding of phase one and phase two detoxification. And while you don’t need to be an expert in this area to do a liver detoxification, having a basic understanding of the pathways involved can help you to have a better detox. In the last post I focused on phase one detoxification, and in this post I’m going to focus more on phase two detoxification.
Before talking about phase two detoxification, I want to briefly summarize phase one detoxification. If you recall, phase one detoxification is a process of biotransformation, as it’s when the liver transforms fat soluble compounds into reactive intermediates with the help of CYP enzymes. In phase two these reactive intermediates are then turned into water soluble molecules so that they can easily be excreted in the bile and feces.
Phase two involves six different pathways. And while I hope you found the first blog post on phase one detoxification to be interesting (and not too confusing), since phase two is more nutrient-dependent I’m hoping that you will find this post to be even more valuable. After all, while the biotransformation process involved in phase one is of course very important, most people who do a liver cleanse are focusing more on phase two detoxification by eating certain foods, along with taking certain supplements and herbs.
The Six Different Pathways Of Phase Two Detoxification
Remember that phase one results in the production of a reactive intermediate. Conjugation is the process where a substrate is coupled with the reactive intermediate, which in turn makes this less active and water soluble. This allows the toxin to be easily excreted, and the actual excretion is considered to be phase three detoxification. So with that being said, let’s go ahead and look at the different phase two detoxification pathways. And probably the most important factor to pay attention to with each pathway is the nutrients involved.
1. Glucuronidation. This process involves a few steps, and if you recall, earlier I mentioned that conjugation involves the substrate coupling with the reactive intermediate that is produced in phase one, and this makes the xenobiotic/chemical less active and more water soluble. With glucuronidation, when the substrate is conjugated with the reactive intermediate it leads to something called a glucuronide. This process also involves an enzyme called Uridine 5′-diphospho-glucuronosyltransferase, which is also known as UGT. There are different types of UGTs, and these enzymes help to catalyze the conversion of the compounds into water soluble molecules.
Some of the compounds that are conjugated in this pathway include bilirubin, thyroid hormone, and the steroid hormones. So glucuronidation helps with the detoxification of thyroid hormone, along with other hormones. If someone has reduced glucuronidation the person won’t be able to detoxify these compounds, which can lead to numerous problems.
But why would someone have reduced glucuronidation, or a reduction in any of the other pathways? Well, there can be a few reasons. One reason is because they are not consuming the required nutrients to support that pathway, which I’ll discuss shortly. Another reason is because someone can have a genetic defect that affects the enzymes involved in these pathways. An example of this is seen with Gilbert’s syndrome, which involves a genetic defect in UGT1A. This results in an impaired ability to conjugate bilirubin with glucuronic acid, and as a result can lead to jaundice. One potential sign of Gilbert’s syndrome on a blood test is when someone has consistently elevated bilirubin levels. If someone has this genetic defect then they not only can have problems conjugating bilirubin, but other compounds as well.
Ideally you want to try to do things to induce, or accelerate glucuronidation. Some of the nutrients and phytonutrients that can help accomplish this include quercitin, curcumin, resveratrol, milk thistle, grape seed extract, and hawthorn. You also want to make sure to consume omega 3 fatty acids, and magnesium. Probiotics and calcium d-glucarate can help to inhibit beta glucuronidase, which I’ll briefly discuss below. Foods which support glucuronidation include apples, kale, broccoli, and watercress.
What is Beta-glucuronidase?
Beta-glucuronidase is an enzyme produced by bacteria in the gut. You ideally want to have low levels of this, and the reason for this is because if this enzyme is active then it results in uncoupling of the substrate and the phase one intermediate, and the toxin therefore gets reabsorbed into the enterohepatic circulation, which isn’t a good thing. In fact, elevated beta-glucuronidase is associated with an increased risk of certain types of cancers. One of the ways to test for beta-glucuronidase is through the Metametrix comprehensive stool panel. Some of the nutrients and herbs which can inhibit this enzyme include broccoli, Brussels sprouts, apricots, watercress, calcium d-glucarate, milk thistle, and licorice.
The Role of Thyroid Hormone In Glucuronidation
Thyroid hormone is also involved in glucuronidation, as T3 influences some of the UGT enzymes (UTG1A1 and UTG1A6). Vitamin A also plays an important role in this (1). As a result, even if someone has sufficient T3 levels, but has a vitamin A deficiency, then this will have a negative effect on glucuronidation.
2. Sulfation. Sulfation involves multiple steps, but the end result is conjugation with the substrate, which as you know by now will make the xenobiotic inactive and water soluble. An enzyme called 3-phosphoadenosine-5-phosphosulfate is a coenzyme involved in sulfation. An enzyme called sulfite oxidase catalyzes the conversion of sulfite to sulfate, which is necessary to break down sulfur-containing amino acids such as methionine and cysteine. What’s important for you to understand are the nutrients required in this pathway, and vitamin B6 and molybdenum are required cofactors for this enzymatic reaction. As a result, a deficiency of either one of these can cause problems with this pathway. Having problems with sulfation can result in food sensitivities, chemical sensitivities, or an intolerance to acetaminophen.
3. Methylation. I’m not going to get into detail about methylation, but I did speak about this process in an article entitled “Methylation, MTHFR, and Thyroid Health“. With regards to detoxification, methylation involves conjugating phase one intermediates with methyl groups. Three of the more important nutrients required to help support methylation include folate, vitamin B12, and vitamin B6. These are the main cofactors of S-Adenosyl-l-methionine (SAMe), which is the main methyl donor. Once again, for more detailed information on methylation I would read the article I wrote on this topic.
4. Glutathione Conjugation. Many people reading this are familiar with glutathione, which is an antioxidant that helps to protect us from free radicals, but also plays an important role in phase two detoxification. N-acetylcysteine is a precursor of glutathione that I commonly recommend to my patients to help support phase two detoxification. Another option is to take an acetylated or liposomal form of glutathione. There are also numerous cofactors of glutathione, including selenium, magnesium, niacinamide, vitamin C, and alpha lipoic acid. Fruits and vegetables usually contribute over 50% of dietary glutathione. In addition, having healthy butyrate levels can also lead to healthy glutathione S transferase levels. Butyrate is a short chain fatty acid that is produced by the gut flora.
5. Amino Acid Conjugation. Not surprisingly, amino acid conjugation requires amino acids such as glycine, taurine, and glutamine. Of these, glycine is the amino acid most commonly used for amino acid conjugation, although taurine is also commonly used. So in order to support amino acid conjugation you want to make sure you are eating enough protein.
6. Acetylation. Acetylation involves conjugating toxins with acetyl Co-A. If someone has a condition such as multiple chemical sensitivity then they will usually be a “slow” acetylator. Acetylation is involved in eliminating excess histamine, serotonin, and sulfa drugs. Nutrients which enhance acetylation include Vitamin C, B1, B2, B5, magnesium, and lipoic acid. N-acetyltransferases (NATs) are drug-metabolizing enzymes that play a role in this pathway.
How Do You Get All Of The Nutrients To Support Phase Two Detoxification?
As for how to get the necessary nutrients to support phase two detoxification, you want to get as many of these nutrients through diet. Eating plenty of fruits and vegetables is of course important, but you also want to make sure you eat sufficient protein as well. While you want to get as many nutrients as you can through your diet, taking nutritional supplements and herbs can also help to support phase two detoxification. Throughout this post I listed nutrients associated with each of these pathways. So for example, to support glucuronidation I mentioned food sources such as apples, kales, and broccoli, but you can also supplement with curcumin, resveratrol, or milk thistle. Similarly, diet plays an important role in methylation, although if someone has an MTHFR defect then they might need to supplement with methyl folate or other supplements.
So hopefully you have a better understanding of phase two detoxification. In phase two detoxification, the reactive intermediates that were formed in phase one are made water soluble so that they can be excreted. There are six different pathways associated with phase two, including glucuronidation, sulfation, methylation, glutathione conjugation, amino acid conjugation, and acetylation. You want to get most of the nutrients to support these pathways through diet, although taking certain nutritional supplements can be beneficial at times.
Is there a test to determine if one is sufficient in all these liver enzymes?