How To Optimize Detoxification: Part

February
16, 2017

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 dont have a good understanding of phase one and phase two
detoxification. And while you dont 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 Im 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 its 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 Im 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, lets 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 wont 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 Ill 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 Gilberts
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 Gilberts 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 Ill 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 isnt 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. Whats 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. Im 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