Thursday, May 19, 2016

Detoxification 101: The basic science behind cellular detoxification

Are you sensitive to mold, perfumes, detergents, or other chemicals in the environment?  Do you suffer from a hormonal imbalance that includes the thyroid, adrenal, and sex hormones?  Have you attempted to rectify the situation by performing a detox, cleanse, or other form of reset with little or no improvement?  Well maybe it's time you learned the finer points of detoxification.  In this blog we'll cover:
  1. The layout of the human body from a detox perspective
  2. The 3 phases of detoxification at the cellular level
  3. The hormone/detox link
  4. How inflammation blocks detoxification
  5. Other factors that likely impede your ability to detox

Once your finished with this blog, you'll have a pretty good handle on the detoxification process and how you can use it to your advantage to improve your health.  You'll also understand how certain supplements or foods that are considered detox powerhouses may not be right for every person.  An individualized approach is best, and sometimes throwing random supplements and foods at the problem can actually make you feel worse.  Let's jump in.

Detoxification at the organ level

The layout of the human body is quite amazing.  You have trillions of cells that all contain the same DNA but look vastly different.  This is because the environment your cells are in dictate what they become through a process called epigenetics.  So even though your skin and liver cells contain precisely the same information, the environment each cell type is in causes each to differentiate in to a completely different type of cell that suits that particular environment.

Along with looking different, each cell type in your body contains different functional elements.  From a detoxification perspective, we are going to focus on something called the steroid and xenobiotic receptor, or SXR.  As the name suggests, the SXR is a receptor that binds steroid hormones and xenobiotics.  Xenobiotics are simply molecules that are foreign to the body.

Something that binds to a receptor is called a ligand.  When a ligand binds to the SXR, it initiates the process of biotransformation.  For a steroid hormone, this means that it recruits enzymes that either activate or deactivate that steroid hormone.  For a xenobiotic, binding to the SXR initiates the 3 phases of detoxification for eventual removal, but we'll get back to that.  What's important to understand is that cells that express high levels of this receptor will be highly involved in the detoxification process, and the process is exactly the same whether you are transforming a steroid hormone, detoxifying a xenobiotic, or metabolizing a pharmaceutical drug.

When we look at cells that express high levels of the SXR, we find 2 separate functional groups.  The first is organs involved in the manufacture and transformation of steroid hormones which include the liver, kidney/adrenals, and reproductive organs.  The second functional group is involved in the detoxification of xenobiotic substances and include the lung, skin, digestive tract, liver, and kidneys/adrenals.  For the moment we'll focus on detoxification, but we'll swing back to the steroid part in a little bit.

The layout of the human body from a detox perspective

From a detoxification perspective, the human body is laid out very well.  The 3 primary barriers keeping the external environment from invading our internal environment are well suited to detoxify xenobiotics because they all express the SXR.  Of the 3 barriers, the one that is most often exposed to xenobiotics is the gastrointestinal tract, and it has nearly the same level of the SXR as the liver which has the greatest expression of SXR and has a central role in detoxification.

Of course, no process is 100% efficient, and the GI tract is no exception.  Whether it be from sluggish detoxification or an impairment in the intestinal barrier, xenobiotics can gain entrance from time to time.  Fortunately, xenobiotics that enter the circulation from the GI tract do so through the portal vein, which immediately goes to the liver for further detoxification.  This doesn't mean that you can't overwhelm the system, and there are numerous xenobiotics that enter the digestive tract on a daily basis.  The ones you need to be primarily concerned with are fat soluble.  This includes what is likely the most ubiquitous xenobiotic to enter the human digestive tract, bisphenol-A(BPA).

Cellular detoxification

When it comes to detoxification at the cellular level, water soluble toxins are really not that much of a concern for a couple of reasons.  First off, all of our cells are surrounded by a plasma membrane made up of fat.  This prevents water soluble toxins from entering in to cells unless there is a transporter for them, and most transporters that bring water soluble molecules in to cells are highly specific to water soluble substances that are created by the body.  The other reason why water soluble toxins aren't much of a concern is because they can be readily excreted in the urine, sweat, or feces.

This brings us to fat soluble toxins.  As the name suggests, fat soluble toxins can freely enter your cells because they are fat soluble and the plasma membrane is made of fat.  When a fat soluble toxin enters one of your cells, the SXR binds to the toxin in the cytoplasm and initiates one or all of the 3 phases of detoxification.  The 3 phases of detoxification include modification, conjugation, and transport/excretion.

Phase 1 detoxification modifies the fat soluble toxin through either oxidation, reduction, or hydrolysis to make the toxin more water soluble.  This is typically done by one of the cytochrome P450 family of enzymes, of which there are 18.  In some instances this makes the toxin less toxic and easy to remove from the cell and the body.  However, there are instances where Phase 1 detoxification isn't enough to remove the toxin from the cell, and sometimes Phase 1 actually makes the toxin more toxic.  A great example of this is the conversion of alcohol to acetaldehyde, which is more toxic than alcohol.

If the toxin cannot be removed by the cell or is made more toxic during Phase 1, Phase 2 detoxification begins.  This further transforms the toxin so that it's readily soluble in water and can be removed from the cell.  Phase 2 conjugation is carried out through 6 different pathways including methylation, sulphation, acetylation, glucuronidation, glutathione conjugation, and glycine conjugation.  Once the offending molecule is conjugated, Phase 3 transporters escort the now water soluble toxin out of the cell.  Since it's now water soluble, it can't enter your cells and is excreted via the urine, sweat, or dumped in to the feces as a component of bile, which is produced by the liver.

The hormone/detox link

As you may have guessed, something called the steroid and xenobiotic receptor is a major link between detoxification and issues with hormonal balance.  Ideally, most fat soluble toxins will bind the SXR in cells of the GI tract and get detoxified, and any that bypass the GI tract are dealt with by the liver and either removed from the body through urine or re-deposited in the GI tract in the bile after being transformed in to a water soluble molecule that cannot re-enter the circulation.  The problem is, things don't always go as planned.

Any fat soluble toxin that makes it past the GI tract and liver, or that enters through one of the other barriers, is capable of interacting with the SXR in any cell that expresses it.  This is problematic in organs involved in the transformation of hormones to active or inactive states including the above mentioned liver, adrenals, and reproductive organs.  When a toxin that is a ligand for SXR enters the circulation, it can bind to the SXR in any tissue and disrupt signaling there.

Probably the best known fat soluble toxin that is also a ligand for the SXR is bisphenol-A or BPA.  BPA is an endocrine-disrupting chemical capable of binding multiple types of hormone receptors, the SXR being one of them.  BPA typically enters the circulation through the GI tract.  However, under normal circumstances, BPA enters the general circulation in its inactive, conjugated form after undergoing phase 2 detoxification in the GI tract and/or liver.

Any BPA that enters the general circulation in the conjugated form will not enter tissues because it's water soluble and has no transporter to bring it across cell membranes.  This makes it readily excreted from the body.  If BPA enters the circulation in its active, unconjugated form, it can enter cells, bind to the SXR, and disrupt the biotransformation of hormones in steroidogenic tissues.  In the reproductive organs, this will lead to fertility issues.  In the adrenal glands, SXR is primarily involved in corticosterone and aldosterone production.  This would lead to the problems associated with HPA axis dysfunction which are primarily due to electrolyte imbalance

Corticosterone is also of particular interest in the skin as it helps regulate inflammation there.  The skin has its own functioning HPA axis similar to the HPA axis that controls cortisol secretion from the adrenals, but the final product in the skin is corticosterone.  In the skin, corticotropin releasing factor(CRF) causes the secretion of adrenocorticotropic hormone(ACTH) which then causes the release of corticosterone.  Corticosterone then feeds back to stop the release of CRF.  Unregulated CRF released causes inflammation in the skin by causing mast cells to release histamine, which is why topical hydrocortisone is used to treat skin inflammation: it stops CRF release via negative feedback due to its structural similarity to corticosterone.

This is all well and good, but the questions remains...How would unconjugated BPA get past the intestinal barrier and liver?

Inflammation and detoxification

Inflammation seems to be the major buzzword in medical sciences these days, and for good reason.  It seems to be one of the underlying causes of many of the disease that are killing us and it disrupts many biological processes in the human body.  If you haven't figured it out yet, one of the processes it affects is detoxification.

It's well known that people with inflammatory bowel disease have impaired detoxification.  The primary reason for this is because the SXR and inflammation are involved in reverse regulation of one another.  Specifically, when inflammation goes up the expression of the SXR drops and when SXR is activated inflammation levels drop.  We know this both through direct evidence from scientific studies as well as the effect of systemic inflammation on pharmaceutical drug metabolism.  Approximately 60% of pharmaceutical drugs on the market today are metabolized by cytochrome p450 3A4(CYP3A4) which is controlled by the SXR, and why wouldn't they be?  Many pharmaceutical drugs are steroids, all are xenobiotics, and a good number of them could be considered both.

So the answer to how unconjugated BPA can get past the intestinal barrier and liver is via inflammation.  Inflammation in the digestive tract impairs detoxification there and increases intestinal permeability.  This allows unconjugated BPA to enter the portal vein while systemic inflammation impairs the livers ability to conjugate BPA once it makes its way there.  The result...unconjugated BPA accesses the general circulation where it can disrupt hormonal signaling throughout the body.
(Quick sidebar: a few years ago the scientific consensus was that BPA was so quickly metabolized that unconjugated BPA never entered the general circulation, despite multiple lines of evidence to the contrary.  Of course, the studies that conflicted with industry studies were disregarded as being due to laboratory error or contamination.  At this point, the science is overwhelming.  The current understanding is that either BPA is not detoxified as rapidly as once thought, that there are other routes outside the digestive tract that allow unconjugated BPA in, or the most likely answer being both.  Regardless, it's entering the circulation unconjugated and disrupting hormonal signaling)

Righting the ship

So what are you supposed to do?  If it's not obvious, one of the first things you need to do is remove sources of inflammation, particularly in the digestive tract as GI inflammation likely contributes to systemic inflammation to a significant degree.  This includes removing or limiting things like dairy, gluten, processed seed oils, or any food you are intolerant to.

The next thing you can do is limit the amount of fat soluble xenobiotics you are exposed to on a daily basis.  BPA is a big one, primarily due to the consumption of food heated in plastic, cooked with plastic utensils, or hot coffee that's exposed to plastic.  This includes coffee made in coffeemakers that use plastic including Keurig brewers, coffee that's stored in plastic dispensers at gas stations and convenience stores, and coffee that's consumed through plastic lids.  Whether these containers are BPA-free or not is irrelevant, the most frequently used replacement for BPA, BPS, has the same endocrine disrupting effects as BPA and seeps from plastic container in to its contents.  Organochlorine pesticides are also a major route of exposure.  Other sources of fat soluble toxins include receipts, cosmetics, detergents and perfumes, although these sources shouldn't be ingested but may enter via the skin. :)

One thing you shouldn't do is just start slamming down detoxification promoting supplements and foods.  Manipulating the detoxification process to improve your health is a highly individualized process dependent on genetic as well as environmental factors and many substances can have a dramatic impact on the way you feel due to these factors.  For example, grapefruit and pomegranate juice are both known to inhibit phase 1 detoxification and can dramatically impact the blood levels of certain drugs, actually a lot of them since they both directly inhibit CYP3A4.  So think about that when your slamming down a bottle of Pom.  Also, feel free to refer this to your friend who says the human body can easily handle all environmental toxins that are thrown at it when simply drinking grapefruit juice can lead to toxic accumulation of pharmaceutical drugs in a very short amount of time.

For someone on chemotherapy or a drug metabolized via CYP3A4, these products can lead to adverse events.  However, for someone like me who is genetically a fast oxidizer, slowing down phase 1 detoxification can reduce the number of products from phase 1 detoxification and allow my phase 2 pathways to catch up, improving fatigue and general well-being due to reduced toxic load.

Another area where Phase 1 inhibitors are useful is people reacting to aflatoxins from mold.  Alflatoxins are made more toxic after Phase 1 reactions and can bioaccumulate if Phase 2 is outpaced by Phase 1.  Different supplements manipulate detoxification in different ways and this needs to be kept in mind when supplementing to improve the way you feel as well as your overall health.

This brings me to a final point...There are 6 pathways of phase 2 detoxification, don't just focus on methylation and glutathione conjugation.  BPA is a great example given that it's conjugated primarily via glucuronidation and sulphation, 2 pathways that use and are induced by different nutrients than methylation and glutathione conjugation.  Supporting these two pathways doesn't do too much for the removal of BPA from the body.  In fact, simply sweating does more for BPA removal than supporting methylation and glutathione conjugation, although glutathione can act as a back up if the other 2 pathways fail.


I hope this blog has given you a deeper understanding of the detoxification process.  If manipulated properly, optimizing your detoxification pathways can transform your health and improve your quality of life.  Blindly following health trends without a basic understanding of what you're doing can prevent you from attaining optimal health and could make things worse.

Fortunately, the absolute first step is relatively easy to do: reduce inflammation.  This is primarily done through lifestyle modification including diet, exercise, stress management, proper sleep, and other lifestyle factors that are associated with inflammation.  People with inflammatory conditions such as IBD/IBS, arthritis, or an active autoimmune condition will almost certainly require some other support which can include pharmaceutical drugs, supplements, or a combination of both.

From there, if you want to work your detoxification pathways, the next step is knowing how detoxification works for your specific issues.  Having your genome done by 23andme and using promethease or genetic genie to look at your detoxification pathways is very useful and can help you identify dietary and supplemental factors that will save you a lot of time and failure in the long run.  It will help you identify which pathways are sluggish and, therefore, which environmental toxins you may be more sensitive to.  There are numerous resources on the web that can get you pointed in the right direction.

The final step is to formulate a plan and give it a go, using how you feel as a guide on your success and recording what you do for future reference.  Also, keep in mind that initiating any program like this should be discussed with your physician so that any drug-drug and drug-supplement interactions can be avoided.