Pathways to Detox Pt. 4:: Phase II Whats and Hows-9194

I never thought I would be one of those writers that did long “series” but let’s face it; liver detoxification is a seriously complex issue.  I started to write all the explanations of what the various conjugation pathways did yesterday and it would have been a novel by the time I was done so I thought I would break it down into digestible bites instead. Nice of me, no?

Yesterday we touched upon the fact that Phase II detoxification in the liver has six different pathways (7 if you break down the amino acid conjugation pathway further) in which to conjugate (add molecules to chemical compounds, used hormones, and other toxins making them metabolizable and able to be excreted by the body) and “package” specific compounds via these different pathways.  

{You can read about Phase I Detoxification and cytochrome P450 in Part 1 and Part 2.}

For those of you who may have missed yesterday’s Part 3 in the series the Phase II conjugation pathways are::

  • Glucuronidation Pathway
  • Amino Acid Conjugation Pathway (broken down further into cysteine pathway and taurine pathway)
  • Sulfation Pathway
  • Acetylation Pathway
  • Glutathione Conjugation Pathway
  • Methylation Pathway (this will have several posts written about it as 40-60% of our population is affected by defects of this pathway)

Today we will break down what each pathway to detox does and the nutrients that help them function better.  

It should be noted, before we begin, that this post is absolutely not meant to be a blanket “supplement plan”.  Not every person will have a deficiency in every nutrient needed to keep pathways running smoothly and some may even have a genetic defect in certain pathways whereby they need specific support to ensure that pathway can open.  Many people may even have a few defects in different pathways and the ORDER in which they are treated becomes crucial, therefore, it is always wise to work with someone who understands the protocols needed to correct certain defects and blockages.  Should you want to delve deeper into your unique situation, you can book an appointment with me and, if needed, we can order the necessary tests and put together a plan for your individual needs.

 Let’s take a look at each individual pathway to detox and their scope of responsibility in the body.

Glucuronidation binds glucuronic acid to toxic metabolites such as acetaminophen, lorazepam (and that family of drugs), codeine, glucocorticoids,  mineralcorticoids, pollutants, androgens, estrogens (more on that later) and fatty acid derivatives.  (Think of trapped PUFAs or ingested PUFAs as toxins in this case.)  This process can be defective with any impairment in the gut (such as leaky gut) by beta glucuronidase enzymes produced by pathological bacteria which cause toxins to be reabsorbed into the body, thereby increasing toxicity. Calcium d-glucarate, a natural ingredient found in certain vegetables and fruits and  supplement can inhibit beta glucuronidase activity which can increase elimination of toxins and unblock the pathway. 

Amino Acid Conjugation utilizes several different amino acids to bind with and neutralize toxins.  (Glycine, taurine, ornithine, glutamine, and arginine)  Of these, glycine is most commonly used in this Phase II pathway.  Disorders such as alcoholic liver disease, hepatitis, arthritis, carcinomas and toxemia during pregnancy along with excess exposure to chemicals typically suffer from an amino acid conjugation system that functions poorly.

A large variation in the efficiency of the glycine conjugation pathway exists even in healthy individuals. This is due not only to genetic variations and anomalies, but also to the availability of glycine in the liver. Glycine, and the other amino acids used for conjugation, become deficient on a low-protein diet (specifically protein that is digestible from bone broth, gelatin, bone-in cuts of meat, quality dairy, if tolerated) and when amino acids are depleted due to chronic exposure to toxins.  This is why I tell my clients when we are working with detoxification issues such as estrogen dominance, consumption of high-quality protein is key for healing.

The Sulfation Pathway conjugates sulfur-containing compounds (say that five times fast) with toxins. This pathway detoxifies several drugs (NSAIDs like Tylenol, Ibuprofein,and Aleve to name a few), food additives (think food dyes and flavorings), and, especially, toxins from endotoxins such as intestinal bacteria,viruses and other organisms. In addition to environmental toxins, sulfation is also used to detoxify some byproducts of metabolism and is the main pathway for the elimination of used steroid and thyroid hormones. Since sulfation is  the primary route for the elimination of used neurotransmitters, defects in this pathway may contribute to the development of several nervous system disorders and can even be a key factor in the development of depression, anxiety, and behavioral issues.

Many factors influence the activity of sulfate conjugation. For example, a diet low in methionine and cysteine has been shown to reduce sulfation. Sulfation is also reduced by excessive levels of molybdenum or vitamin B6 (over about 100 mg/day). In some cases, sulfation can be increased by supplemental sulfate, extra amounts of sulfur-containing foods (think onions and garlic, asparagus, cabbage and other brassica veggies, etc.) in the diet, and the amino acids taurine and glutathione. (We will be talking about the significance of glutathione in a subsequent post.)  I will address the very common defect in the sulfoxidation process whereby sulfites are not metabolized properly into safer sulfates and there is an elevated ratio of sulfites to sulfates in urine.  In westernized culture as sulfites are everywhere from pharmaceuticals to food preservatives, to dried fruits and drugs, this is most illustrated by the asparagus smell present in urine after eating it.  In China, where sulfites are not ever present, the asparagus smell is not reported yet, in France, where sulfites in wine abound, the smell is reported in the majority of cases.

The Acetylation pathway is responsible for the conjugation of Acetyl-CoA with toxins and is the primary method by which sulfa drugs are eliminated by the body. This is one of the most sensitive pathway to genetic variation and defect.  When there is any defect in this pathway a general intolerance to sulfa drugs (and even other antibiotics) is problematic.  Acetly-CoA  is at the center of lipid metabolism (which means it is the precursor to steroidal hormones and bile acids) and can be converted to fatty acids raising triglycerides, phospholipids, prostaglandins, and ketones (when not in balance).

The Glutathione Conjugation Pathway is the primary pathway of Phase II detoxification path. It conjugates toxins with glutathione, which is considered the master antioxidant, (a tripeptide composed of three amino acids–cysteine, glutamic acid, and glycine). 

Glutathione conjugation produces water-soluble metabolites which are ushered to the kidneys and excreted in urine.  Heavy metals like mercury and lead, fat soluble compounds are eliminated efficiently only when there are adequate levels of glutathione.  Adequate levels of glutathione are dependent upon adequate levels of methionine and cysteine. Toxic overload creates a perfect storm where more a need for more methionine is created for cysteine and glutathione synthesis. Methionine and cysteine are protective of glutathione and prevent depletion during toxic overload. This, in turn, protects the liver from the damaging effects of toxic compounds and promotes their elimination. Not complicated at all, right?

Glutathione is, as I said, is considered the master antioxidant. It offers both free radical protection and detoxification support and is considered to be one of the most important anticarcinogens and antioxidants in our cells. Because glutathione is this vital of a nutrient a deficiency can cause some serious liver dysfunction and damage. When we bombarded by chemicals and other toxins glutathione is depleted faster than it can be produced or absorbed from what we eat. When this happens, toxin induced diseases ensue such as cancer.  This is even more of a problem when Phase I (cytochrome P450) is very active. Glutathione deficiency and dis-ease that is created by such a deficiency is much more common than you think.

Glutathione deficiency can be created either by disorders and diseases that increase the need for glutathione, deficiencies in the nutrients needed for  glutathione synthesis, or diseases that inhibit its formation. Smoking increases the rate of glutathione usage, both as a result of the detoxification of nicotine and the need to neutralize the free radicals produced by the toxins in the smoke. Glutathione can be obtained by both diet and synthesis. Dietary glutathione (found in fresh fruits and vegetables, cooked fish, and meat) is highly absorbable by the intestines and does not appear to be affected by the digestive processes. Glutathione obtained by diet is efficiently absorbed into the blood but supplements that must undergo the digestive process are not so metabolizable. 

In healthy individuals, Vitamin C (500 mg. daily) may be sufficient to raise and maintain positive  glutathione levels in tissues. Double-blind studies have indicated the average red blood cell glutathione concentration rose nearly 50% with 500 mg/day of vitamin C.  Higher dosages ( up to 2,000 mg) only raised red blood cell  glutathione levels by another 5%. Vitamin C increases glutathione’s rate of synthesis which increases its level in tissues. In addition, to vitamin C, other compounds help increase glutathione synthesis including N-acetylcysteine (NAC), glycine, and methionine.  Those with impaired glutathione synthesis may benefit from Vitamin C an NAC supplements in a bid to increase antioxidant status but studies are still sketchy on which cases work with these supplements. 

Over the past 5-10 years, the use of NAC and glutathione products as antioxidants has become increasingly popular among nutritionally oriented physicians and the public. While supplementing the diet with high doses of NAC may be beneficial in cases of extreme oxidative stress (e.g. AIDS, cancer patients going through chemotherapy, or drug overdose), it may be an unwise practice in healthy individuals. 

Glutathione supplementation is best done via IV via a physician who specializes in detox issues.  In my practice I find the use of glutathione suppositories nearly as effective as IV chelation.  

Methylation involves conjugating of toxins to methyl groups. Most of the methyl groups used for detoxification are derived from from S-adenosylmethionine (SAM). SAM is synthesized from the amino acid methionine, a process which requires choline, the active form of B12 –methyl cobalamin, and the active form of folic acid –5-methyltetrahydrofolate (L5MTFHF). SAM is able to inactivate estrogens (via methylation), supporting the use of small amounts of methionine where estrogen dominance is problematic, such as PMS.  In addition to its role in promoting estrogen excretion, methionine has been shown to reduce many symptoms associated with estrogen dominance including membrane fluidity which results in stagnation of bile within the gall bladder. Methionine also promotes the flow of lipids to and from the liver. Methionine is a major source of numerous sulfur-containing compounds, including the amino acids cysteine and taurine. A word of warning here.  A little methionine is good.  (Gelatin and collagen  contain small amounts.)  More is not better.  Methionine, in excess, can prevent proper methylation and is inflammatory to the body, including thyroid.

We will be talking at length about methylation as, when this pathway is defective, it can be so in many different ways.  Left to the inexperienced trying to treat detox pathways, it can be particularly disastrous as methylation often should be addressed last when there are a string of defects present.  If you suspect you might have a pathway defect booking an appointment with me can get you tested and on the right path to healing.

In our next post we will be discussing how estrogen is detoxified by these pathways and what happens when defects are present and how they affect estrogen levels in the body. 

Is your brain ready to explode yet?  Stay tuned!

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