DETOXIFICATION / BIOTRANSFORMATION PATHWAYS
IGNORE THESE CRITICAL LIVER
FUNCTIONS AT YOUR OWN PERIL
Unfortunately, our collective livers are under assault, not only from the thousands of chemicals we expose it to regularly, but from our typically crappy diets. For instance, a 2014 issue of the World Journal of Gastroenterology says this of Non-Alcholoic Fatty Liver Disease (NAFLD). "Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of liver disease in the Western world. Furthermore, it is increasing worldwide, paralleling the obesity pandemic. Of relevance, fatty liver is also associated with increased overall mortality and particularly increased cardiovascular mortality and is strongly associated with insulin resistance / type 2 diabetes and the metabolic syndrome [PREDIABETES]." Same journal, same month, different authors.... "In the United States, NAFLD is the most common cause of liver disease, representing over 75% of the chronic liver disease." In other words, even though you probably learned growing up that alcoholism is what destroys livers, in the big picture it accounts for a relatively small percentage. OBESITY is what destroys livers (even if you are "SKINNY").
The question arises, what can we do to keep our livers functioning optimally? It should be obvious that maintaining a healthy weight is paramount. Beyond that the research talks at length about many of the same things I talk about on my site ---- controlling BLOOD SUGAR and staying far away from the HIGH CARB LIFESTYLE, GUT HEALTH, INFLAMMATION (this covers huge amounts of ground), EXERCISE, and any number of others (SLEEP APNEA has also been associated with NAFALD, possibly because it's so intimately linked to obesity). Today I want to talk about some of the detoxificiation / biotransformation pathways and show you, using the scientific literature, what you can do to support them.
I'll start with a brief overview taken from THIS POST written about what it takes to clear out excess female hormones and artificial female hormones. The same principles are at play for virtually every toxin and chemical in your body, whether made from within or there from the outside exposure.
- PHASE I describes the first step of your body's ability to turn various toxins to forms that can be excreted from the body. It is the body's first metabolic defense against foreign chemicals. Phase I reactions are primarily performed by via oxidation (oxygen) and the P450 Cytochrome Enzymes. This involves either adding or "uncovering" an active site so that the various components of Phase II can do their job.
- PHASE II reactions attach or "conjugate" the toxins to various compounds in order to increase their ability to be voided. This part of the equation is where the oxidized chemicals are combined with sulfur, specific amino acids, or organic acids, so that they can be excreted in the bile and eventually the feces, or in the urine. There are several different enzymes and different metabolic pathways for accomplishing this that can and will become depleted without replenishing them via a nutritious diet. Phase II can be inhibited by alcohol, drugs (prescription, OTC, or recreational), and nutritional deficiencies (including too little dietary protein).
- PHASE III is simply the process of your system actually removing / excreting the conjugated toxic chemicals from your body ---- without reabsorbing them. Be aware that this is virtually impossible without ample amounts of dietary fiber (something you must be careful of with SIBO / IBS).
As a side note, the field of Toxicokinetics or Pharmacokinetics studies how rapidly and effectively certain substances can be cleared from the body, or whether they or their metabolites accumulate in fatty tissue. I also want to take just a moment to discuss the term xenobiotics, since they will come up over and over again.
Xenobiotics are defined in many ways and can be chemicals (toxins) that should never be found in the human body, chemicals that should be there but are present in amounts that are far too high to be considered normal (ESTROGEN DOMINANCE), or chemicals that are put into your body on purpose but are not found there naturally (MEDICINES / ANTIBIOTICS). You will frequently hear the term xenobiotic and ENDOCRINE DISRUPTOR used synonymously.
Other xenobiotics include things like known carcinogens, cigarette smoke, pollutants, food additives, hydrocarbons (byproducts from oil and gas / gasoline), as well as pesticides and herbicides. Current research says that there are between eighty and ninety thousand chemicals that did not exist prior to WWII with an additional two thousand or so created annually. Thus, the question we need to be constantly asking ourselves is two-fold; what can we do to diminish our exposure, and what do we need to do to insure our Biotransfer / Detox pathways are working optimally in order to clear toxicity from our systems?
PHASE I DETOX / BIOTRANSFORMATION PATHWAYS
- OXIDATIVE REACTIONS (OXIDATION or OXIDIZING): Increasing the oxidation state of the toxin being worked on involves a net loss of electrons. The enzymes involved in this are Aldehyde Oxidase (AO), Flavin-containing Monooxygenases (FMOs), Monoamine Oxidases (MAOs), Xantine Oxidase (XO), and the most important and well known of the lot, the P-450 Cytochrome System (CYP450). These reactions tend to happen a bit slower, and are by far the most common and well known of the Phase I reactions. Oxidation is the most common of the Phase I pathways and happens to be the route whereby most xenobiotics are dealt with. Also realize that while oxidation is vital and necessary, it can present problems as well. Examples of oxidation reactions include rust on metal and the brown color of the part of the apple you took a bite of and then set down for a few minutes.
- REDUCTION REACTIONS (REDUCING): An increase in the reduction state of the toxin being worked on involves a net gain of electrons. These reactions involve enzymes such as Carboxylesterase, Peptidase, Epoxide Hydrolase, Choiniesterease, Paraoxonase, Alcohol Dehydrogenase, and Carbonyl Reductase.
- HYDROLYTIC REACTIONS (HYDROLYSIS): This simply means that chemical bonds of toxins are being broken down by the addition of water --- hydro (water), lysis (to unbind).
- OTHERS: Although there are others, we are not too concerned with them right now.
Of all these reactions, the one that you will hear about most often (by far) is the P-450 Cytochrome System, which also happens to be used for things like the production of CHOLESTEROL, steroid hormones (sex hormones and adrenal hormones), vitamin D, and fatty acid production (Cholesterol is the precursor of everything on this list). Like Hemoglobin, the molecule that carries oxygen throughout the body, the CYP450 molecule has a iron / heme center --- one more reason why ANEMIA is a deal-breaker as far as solving chronic health issues is concerned.
CYP-450 enzymes are found mostly in the small intestine and the liver, with as great as 5% of the total number of liver proteins said to be of the CYP450 family. As strange as it might seem, one of the tests used to see how well a person's Phase I CYP450 Cytochrome System is working is with coffee / caffeine as indicated by any number of studies (for instance Caffeine as a Marker Substrate for Testing Cytochrome P450 Activity in Human and Rat in a 2008 issue of Pharmacological Reports). You can test yourself to some degree. People who are really affected by coffee tend to have less ability to clear toxins via their CYP450 system. Likewise, those who are unaffected tend to clear Phase I faster.
If the intermediate metabolites created by Phase I outstrip the ability of Phase II to conjugate, the body will be exposed to increasingly higher levels of said metabolites as they back up and accumulate. One of the more common intermediates of Phase I is Free Radicals. Free Radicals are relatively simple to understand. Electrons never like to be alone, always wanting a partner to cozy up to. So when an electron is "free" or unpartnered, rest assured that it will be on the prowl for any available electron to pair up with. Unfortunately, these "Free Radicals" will attach themselves to an almost unlimited number of electrons, often times making compounds that can be very toxic. Free Radicals are always looking for stability (pairing up), even at the expense of other compounds. When the body's natural chemistry is robbed of it's electrons, these chemicals --- needed for normal metabolism --- no longer work. While the production of Free Radicals is a normal part of Phase I, anything that inhibits the conversion of the Free Radical to safer compounds is a problem.
When too many Free Radicals build up (CRUDDY DIETS, EXPOSURE TO RADIATION, STRESS, DRUGS (yes, prescription drugs), ANTIBIOTICS, overtraining (too much exercise), coffee, alcohol, and even CHRONIC PAIN), metabolic deficiencies, it creates something called "Oxidative Stress". In other words, the body can't get rid of these toxins by pushing them over to Phase II. Not only is Oxidative Stress associated with inflammation, it is associated with almost every chronic illness we can think of today --- the biggest being cancer. This is why we need the power of antioxidants in our diets --- things like YELLOW SPICES, FRUITS AND VEGGIES with plenty of color, certain berries, along with other foods that have a high ORAC value (Oxygen Radical Absorbance Capacity). There are lots of them. While cocoa can be a fantastic antioxidant, it needs to be at least 85% dark to be beneficial. And while there are any number of chemicals shown to be good antioxidants, the scientific literature has shown that these frequently do not work well in isolation (HERE).
Although there are many toxins / chemicals that are ready to be removed from the body after Phase I, many others (intermediate metabolites) will move on to Phase II, which consists of things like thiol conjugation, methylation, glucuronidation, glutathione conjugation (the heavy-hitter of the bunch), amino acid conjugation, sulfation, or acetylation. Today we are going to spend most of our time in the mythylation and Glutathione pathways.
It is important to be aware that the 'intermediate metabolites' created by Phase I can actually be more toxic to your system than when they were previously. This is why it is absolutely vital to have Phase II working properly. When Phase I is not working properly (or is working in overdrive while Phase II is suppressed), your chances of developing any number of serious diseases, including AUTOIMMUNITY, CANCER, PARKINSON'S, and many others, increases dramatically. Not surprisingly, there is even evidence showing that AUTISM is related to a diminished ability to undergo proper Biotransformation.
PHASE II DETOX / BIOTRANSFORMATION PATHWAYS
This is the big boy; the heavy-hitter of phase II that is said to account for over 60% of the toxins in the bile as well as MERCURY, ALUMINUM, ARSENIC, industrial wastes, and the xenobiotics we spoke of earlier. An amazing thing about the GLUTATHIONE PATHWAY is that it takes an extremely toxic byproduct of aminio acid metabolism --- homocysteine --- and if it has the proper nutrients and enzymes, converts it to Glutatione and SAMe (S-adenosyl methionine), which has several health benefits of its own as far as Phase II is concerned. However, when this conversion is blocked or hindered to varying degrees, homocysteine levels will rise, causing all sorts of health problems (homocysteine is easy to test via blood work).
For instance, when people have a high toxic burden, Glutathione is depleted faster than it can be consumed dietarily (or recycled from homocysteine / cysteine as I just showed you above). If you want to see just how big a deal Glutathione depletion is, cruise on over to PubMed and search "Glutathione (disease of choice)". For instance, a search for "Glutathione Alzheimer's" pulled up over 1,200 studies. I'll show you just one. Last month's issue of Neuroscience and Biobehavioral Reviews (The Effect of N-Acetylcysteine (NAC) On Human Cognition - A Systematic Review) concluded that 12 studies of Alzheimer's patients treated with NAC --- a metabolic precursor to Glutathione --- showed, "statistically significant cognitive improvements following treatment." Not to freak you out, but when I plugged in "Glutathione Cancer," it resulted in nearly 21,000 studies.
WHAT THE HECK IS METHYLATION?
Let me first say that if you really want to understand methylation (I do not consider myself an expert in the least), you need to follow Dr. Suzy Cohen (pharmacist and specialist in FUNCTIONAL MEDICINE), Dr. Ben Lynch (a naturopath with a degree in cellular and molecular biology), Dr. Datis Kharazzian (FUNCTIONAL NEUROLOGIST, Functional Endocrinologist, Chiropractor, Harvard researcher, and author of THYROID BOOK and Why Isn't My Brain Working?), or Dr. Amy Yasko (a Ph.D in Microbiology / Immunology / Infectious Disease as well as a Naturopathic degree, her curriculum vitae reads like a veritable Who's Who. Among others, she worked on the autism front with DR. HUGH FUDENBERG at South Carolina University as well as being a researcher at Yale). Since I have the brain power of a peanut compared to people like this, I am going to give you the Methylation For Dummies condensed version (those in the know might say it's closer to the Mad Magazine version).
With a lot of talk about methylation and MTHFR (methylenetetrahydrofolate reductase) these days, it would behoove us to know a bit about this as it relates to Biotransformation and Detoxification. I've seen experts say that nearly half of the population contains mutations in the MTHFR family of genes. While this sounds scary on the surface, the most important thing to remember is that EPIGENETICS TRUMPS GENETICS, meaning that in many important ways, you are not nearly as defined by your DNA as you have been led to believe, and that "bad genes" are usually switched on via bad lifestyle choices. But why do problems with MTHFR or methylation matter in the first place?
Not that the average Joe cares, but a methyl group consists of a carbon atom surrounded by three hydrogen atoms (CH3), which is structurally related to methane gas. Methyl groups are important in almost every physiological function that occurs in the body, and a failure to methylate properly is indicative of such a wide array of illnesses that it almost not worth listing them. These include neurological, endocrinological, malfunctioning thought processes, inflammatory, and mood disorders. Oh; and for the record, methylation dysfunction is not always genetic, but can be due to deficiencies in methylfolate (a vitamin catalyst) and subsequently Glutathione as well as others. Also realize that the most commonly methylated compound in the body is one we talked about earlier, SAMe.
A common method of treatment for methylation disorders is to essentially bypass both the MFTHR issue and your body's natural feedback loop by giving megadoses of folic acid (you always hear about folic acid --- VITAMIN B-9 --- being a critical part of fortified foods, including ORANGE JUICE, to prevent neural tube defects). This is why you need to use natural or food sources of folate (methylfolate aka 5-MTHF). A deficiency of folate is related to a specific kind of anemia, which is also related to STOMACH ACID PROBLEMS.
Some of the best foods for pumping up your methylation and Glutathione pathways include.... REAL FOOD. The internet abounds with lists of foods, herbs, and supplements that boost the methylation and Glutathione pathways. I discussed this earlier and showed you that while supplements can get you through a pinch, they are not typically the best long-term solution. Now allow me to share with you a quick note about liver as related to liver nutrition.
German Physician, Dr. Max Gerson, wrote his famous book (I own it --- preface by his amazing daughter CHARLOTTE) about sixty years ago; A Cancer Therapy: Results of Fifty Cases and the Cure of Advanced Cancer by Diet Therapy. The basis of his "cure" was organic WHOLE FOODS as opposed to SYNTHETIC NUTRITIONAL SUPPLEMENTS. The thing, however, that sticks out in my mind was the way he used liver. Liver was the foundation of his remedy --- raw and blended into a drink. I am certainly not suggesting anyone do that, but what I am suggesting is that if you can get your hands on completely organic beef liver (no hormones / meds) and eat it regularly, there are some amazing health benefits. Same with some of the other organ meats as well.
An article written by Kevin Cann for Paleo expert, ROBB WOLF (Understanding and Combating Oxidative Stress in Huntington’s Disease) echoed some of these sentiments in a quote from a conversation with medical doctor and MS expert (she essentially cured herself), TERRY WAHLS. Dr. Wahls said to Cann, "When I used supplements – I slowed my decline, when I designed my food supply to get those same nutrients – my strength began to return. Print that and put up where you work – stare it every day. The supplement studies are best used to guide how we create the food plans." An amazing truth from an amazing woman!
OTHER BIOTRANSFORMATION /DETOXIFICATION PATHWAYS
Truth is, there are several different pathways for Biotransformation and Detox.
- The Amino Acid Conjugation Pathway requires ample protein to get the five aminos involved --- the most important being glycine.
- The Sulfation Pathway (similar to the Thiol Conjugation Pathway) uses sulfur-containing foods (many of the cruciferous veggies, for instance, or eggs) and helps conjugate all the nasties we've already discussed, as well as dealing with your body's natural hormones and neurotransmitters. It happens to be a critical part of your body's ability to manufacture proteins and protein / carbohydrate complexes as well.
- The Acetylation Pathway uses acetyl-CoA instead of a methyl group to do its work. People with problems in this pathway tend to not conjugate antibiotics very well, as well as affecting the conversion of SEROTONIN to melatonin --- critical for the sleep / wake cycles known as Circadian Rhythms.
- The Glucuronidation Pathway uses glucuronic acid to attach itself to toxic substances, particularly PAH's (Polycyclic Aromatic Hydrocarbons such as creosote, exhaust fumes, petroleum byproducts) and nitrosamines (found in cosmetics, pesticides, rubber products and tobacco products --- both smokes and chew).
PHASE III BIOTRANSFORMATION / DETOXIFICATION
The first references I saw to this system in peer-review were in the late 1980's (they were talking about how this system could adversely affect the potency of chemotherapy drugs). Just after I started practice in the early 1990's, there were a pair of studies in Trends in Biochemical Science (The ATP-Dependent Glutathione S-Conjugate Export Pump and The Phase III Detoxification System) that stated, "The glutathione S-conjugate export pump (GS-X pump) plays a physiologically important role as a member of the 'phase III' system in xenobiotic metabolism as well as in the release of biologically active endogenous substances from cells. In addition, this export pump is potentially involved in the modulation of the antiproliferative action of certain antitumor agents." In other words, both exogenous chemicals (coming from outside your body) and endogenous chemicals (made by your body) are removed via Phase III.
Sometimes Phase III is referred to as the Antiporter System, and contains something like 350 different proteins, the most common being P-glycoprotein. These proteins typically hang out in the intestinal wall (epithelial lining) and grab hold of the conjugated chemicals so they can be kept in the digestive tract and eventually out in the feces instead of being reabsorbed by the body, back into the blood stream, where the process can start all over again. This is also another of the reasons, as mentioned earlier, that good bile production is needed by the liver (bile is important for good bowel function as well --- HERE). In Dr. Danny Urbinder's article for FX Medicine (What is Phase III Detoxification?), he states.....
"According to Dr Chris Shade, an environmental and analytical chemist who specializes in the human detoxification system, the most significant cause of Phase III dysfunction is inflammation, especially in the gut. When Phase III is blocked a negative feedback loop results in the down-regulation of Phase II enzymes. Intermediate metabolites produced in Phase I are then at risk of building up resulting in increased oxidative damage, which further impairs detoxification capacity."
Your intestines are constantly using energy to keep minerals, water, nutrition, and other "good" substances in your body, while getting rid of waste products, including the toxic byproducts of Biotransformation and Detoxification. Furthermore, if you are familiar with my site, you already realize that I tend to talk a lot about inflammation --- particularly as it relates to GUT HEALTH. If you can keep your Gut and liver clean and healthy, and your body free of inflammation, you are far more likely to be able to clear the junk that we citizens of 21st century earth are exposed to virtually every minute of every day (think about how much more toxic our lives are than they were throughout most of human history).
If you feel you've done due diligence as far as taking charge of your health (HERE), but cannot seem to get over the hump, it's not rare to have issues with these various pathways. Fortunately, there are some very cool oral swab, blood and saliva genetic tests available that can reveal whether or not an inability to detox might be at the root of your problem (currently 23 and me seems to be the best and least expensive option on the market). There are also some very cool tests by Cyrex Labs that reveal if you are making antibodies against some of the more common toxic chemicals such as BPA. Also, the OAT test for organic acids as well as a COMPREHENSIVE GI / STOOL TEST can be beneficial as well.
Finally, remember that this article was not in any way, shape, or form, meant to be definitive, but only to give you an idea of where to start researching. Hope it was helpful.
I completely realize that some of this was technical; probably even a bit boring. I've been putting off writing this for quite some time but decided it was time since these problems are so common. If you know someone who could benefit from this information, be sure to share it with them. The easiest way to reach those you love and care about most is with FACEBOOK.