Liver Detoxification Pathways

Mr. Generic: Could you please explain what Phase I and II liver detoxification pathways are?

Sally: Phase I is equivalent to putting your garbage in a bag and Phase II is like carrying it out of the house. In Phase I toxins are altered so they can attach to carrier molecules to be transported out in Phase II. Phase I uses a family of enzymes called “cytochrome P450.” Phase II has many different mechanisms — 4 of them are measured in the Great Smokies Laboratory’s “liver detox panel test” — conjugation with sulfate, glucuronide, glycine and glutathione. These should be balanced and working optimally. Phase I is measured in the “liver detox panel test,” too. If Phase I is too rapid compared to Phase II, it can cause excess free radical activity.

Liver Detoxification Diagram
Toxins –> Phase I –> Highly Reactive Toxins –> Phase II –> Conjugated or relatively benign Substances –> Phase III

Polly: The water-soluble outputs of Phase I are excreted by the kidneys. The fat-soluble output products of Phase I are further processed in Phase II. The fat-soluble outputs of Phase I can be more poisonous than the original toxins. These intermediate substances are highly reactive — they produce a lot of free radical activity. That is why it is so important to make sure that these intermediate products are removed by Phase II as soon as they are generated by Phase I. If Phase II detoxification is not working fast enough, the products of Phase I will accumulate and harm the liver. You may end up with multiple chemical sensitivity if this happens. Therefore, it is very important that you don’t increase Phase I unless Phase II is working well enough to handle the increased load. ie Don’t take just any product that says it improves “liver health” because it might induce too strong a Phase I reaction in you.

If you don’t have the results of a liver function test to guide you, then the best place to start is:

1) Improve Hormonal Status: Thyroid improves both the liver‘s Phase I and Phase II.

2) Improve Phase II Detoxification: Substances that improve Phase II detoxification are sulfates, TMG, SAMe, lecithin, B12, B6, magnesium, folic acid, taurine, Ulva Rigida, calcium-d-glucarate, and things that help you increase glutathione. Garlic oil, rosemary, cabbage, and brussels sprouts also enhance Phase II activity. [12] Lowering inflammation improves Phase II. Some substances that lower inflammation are: probiotics, transfer factor, IgA, colostrum, bromelain, pancreatic enzymes, progesterone, Mead oil, coconut oil, and emu oil. The fat-soluble vitamins in fish liver oil (A, E, D, and K) also control inflammation, although too much fish oil can be hard on the liver. Bioflavonoids help control inflammation, but these must also be removed by the liver, and may place a strain on the capabilities of the liver. You will have to experiment and find that which you can tolerate in this list.

3) Improve Anti-oxidant Status: Nutrients that improve anti-oxidant status are vitamin A, C, E, coenzyme Q10, taurine, glutathione, selenium, NADH, and lipoic acid. They will help protect you from the free radical activity of the substances put out by Phase I. A small amount of bioflavonoids also improve anti-oxidant status, but they aren’t always appropriate.

4) Reduce Exposure To Toxins: This is only common sense. If there are fewer toxins to process, you don’t overburden the liver. This means avoiding pesticides, heavy metals, and toxins in everyday household and personal care items. It also means reducing your exposure from toxins generated in the gut by harmful bacteria and yeast. Charcoal, fiber, and a decent intestinal transit time will help. The transit time needs to be slow enough that the food is digested, but fast enough that there isn’t time to reabsorb all the toxins that the liver has dumped into the intestines.

Mrs. Generic: What do you do if you Phase I is working much faster than Phase II?

Polly: You try to improve Phase II. Also, try to limit exposure to toxins that will make Phase I work too fast. Eliminate exposure to exhaust fumes, paint fumes, tobacco, carbon tetrachloride, organo-phosphorus pesticides, and the preservatives BHT and BHA. Increasing the use of anti-oxidants will help protect you from some of the Phase I products.

Mrs. Generic: Can you take things to slow down Phase I?

Polly: In general, you don’t want to interfere with the ability of the liver to perform its Phase I detoxification functions. However, sometimes you have to choose the lessor of two evils. If Phase II is so slow or Phase I is so fast that there is an excessive buildup of the Phase I intermediate outputs, then you may be suffering from many chemical sensitivities, and may have to consider slowing down Phase I. This would be only a temporary solution while you work on getting Phase II working.

Taking 500 mg of niacinamide 3 or 4 times per day will inhibit the enzymes in Phase I. [20] Certain bioflavonoids can interfere with Phase I enzymes. Bioflavonoids are also anti-oxidants and can reduce inflammation. For this reason, a modicum of bioflavonoids might be helpful. Something as simple as a half grapefruit per day can be protective.

Be sure to consult with your physician before experimenting with any Phase I inhibitors since interfering with Phase I enzymes can slow the clearance of drugs. Example: doctors will tell you not to take grapefruit juice when using certain medications. Grapefruit juice interferes with the Phase I enzyme that clears/detoxifies most drugs. Milk thistle also interferes with this same enzyme, and should be approached with particular caution when taking prescription drugs.

Mr. Generic: What do you do if you have the opposite problem and Phase II is working well, but your Phase I is slow?

Polly: Phase I can be increased by protein, oranges, tangerines, broccoli, brussels sprouts, saturated fats, sassafras, schizandra, glucocorrticoids, ginseng, licorice, vitamin B2, B6, B12, folic acid, phospholipids, branch chain amino acids, niacin or NADH (coenzyme niacin). [21,22] You can also attempt to get rid of the things that slow down Phase I. These are heavy metal toxicity, estrogen (birth control pills), certain bioflavonoids (quercetin, milk thistle, grapefruit juice), iron deficiency, sugar excess, partially hydrogenated fats, bacteria toxins, niacinamide, Nizoral, and Diflucan. [22] Some interfere with many of the phase 1 enzymes, and others are more specific. For instance, large doses of niacinamide would be expected to interfere with many of the enzymes, whereas Nizoral interferes with the 2C19 enzymes, and Diflucan interferes with the 3A enzymes.

Mrs. Generic: What is Phase III?

Polly: Not much is known about Phase III. One known process is the further metabolism of glutathione conjugates. Another is the further metabolism of sulfate conjugates. Referring to a possible function of Phase III of the liver, Professor Sit Kim Ping, of the National University of Singapore states,

“the efflux of sulfate conjugates of several phenolic compounds has been demonstrated to be ATP-dependent.” [23]

This means that if you have low cellular energy, your liver will have problems removing phenolics like estrogen, bioflavonoids, and food colorings with sulfation. Many of the mercury poisoned and the autistic have a problem removing phenolics. Could it be partially due to low cellular energy?

Jock in UK: There is more about the detox process in these links,…/liver.htm Article “Nutritional Approaches to Liver Detoxification” by Helen Kimber, Positive Health, a magazine based in the United Kingdom, phone +44 (0)117 983 8851 Article on the liver. “The Detoxification Enzyme Systems” by DeAnn J. Liska, PhD, Alternative Medicine Review. 1998…index.html Article on the liver. “The Importance of Replenishing Phase 2 cofactors” Functional Medicine Research Update, Spring 2000…ndex2.html Article on the liver. “Detoxification Profile” Great Smokies Laboratories. Article with a lot of information about the liver, even though the title of the article is “Glutathione” by Parris Kidd, Alternative Medicine Review 1997…ndex3.html Article about one of the detoxification functions of the liver. “What is Detoxication by Methylation? Nutrition and Metabolic Newsletter, Great Smokies Laboratory Issue 2, No. 2 – April 2000…ndex4.html Article about one of the detoxification functions of the liver. “How does Sulfation Work?” Nutrition and Metabolic Newsletter Issue 2, No. 2 – April 2000…aham62.htm Article. “Candida: Diagnostic and Therapeutic Approaches” by Nigel Abraham MSc, FIBMS Positive Health, a magazine based in the United Kingdom.

Polly: Those are exceptional articles. One point struck me as particularly interesting. When the Phase II glucuronidation pathway is overloaded, more of the work falls to the Phase II sulfation pathway. Then if the Phase II sulfation pathway becomes overloaded, more of the work falls to the Phase II glutathione conjugation pathway. The use of this last pathway will deplete the available glutathione and make us more susceptible to the free radicals produced by Phase I.

This has implications for all of us, but particularly for those who are mercury poisoned. All of us are probably somewhat low on sulfates because of the intestinal inflammation, but those with mercury poisoning can be very low on sulfates because the body is dumping the sulfates in the urine. It seems that if you could improve the glucuronidation and bring the sulfate levels back up, then you would have a better chance of improving glutathione levels. Better glutathione levels in the mercury poisoned are very important. The glutathione levels should be up before you start the mercury chelation, or else the recirculating mercury will damage the nervous system. (Another way to spare glutathione is to avoid estrogens and to take a balanced amount of coenzyme Q10, NADH, lipoic acid, vitamin C and E.)

Please leave a comment...