Liver phases 1 and 2 detoxification pathways

The liver phases in a nutshell

Your liver is your most important organ of detoxification and continuously processes all forms of substances, from your digestive tract and the rest of your body, throughout the day. It has to deal with all these compounds, some of which are very toxic and others which are beneficial, and decide what to do with them. Your liver is very good at deciding what needs to be kept and what needs to be removed. It functions like a massive chemical plant that manufactures certain compounds, detoxifies dangerous compounds, and directs substances all over the body for use, storage or excretion. Your liver makes use of two pathways in order to carry out its detoxification work – phase 1 and phase 2 pathways. You can think of phase 1 as being responsible for breaking things down and then sending the raw materials to phase 2, which builds new substances from the raw material by adding molecules to them (this is called conjugation).

Phase 1 uses many, many enzymes to break substances down. This phase as the ‘SUBTRACTION’ phase of metabolism, where the enzymes work to subtract molecules from substances and break them up into smaller more useful units, just like the process of food digestion does so in the gut. Phase 1 is utterly dependent on these ENZYMES, whose speed of metabolism is in turn affected by things like genetics, exercise and the presence or absence of certain substances/supplements in the diet that can either speed them up (induce them) or slow them down (inhibit them). After the enzymes have broken down some of the substances, some very toxic end products (metabolites) remain and they must quickly be shunted to phase 2 pathway in order to make them safer for the body to use. Heavy metals in particular can make these enzymes dysfunctional.

Phase 2 is the ADDITION or CONJUGATION phase where new substances are added/conjugated to the toxic and good metabolites produced in phase 1 in order to make them easier to transport, more stable and/or more functional for the body.
You can think of the phase 2 pathways like you would seven conveyor belts in constant motion extending outwards from a central point, where the phase 1 pathways empty their byproducts. Specific substances are shunted towards a specific conveyor belt where particular enzymes are available for the addition of a ‘special substance’ to create a new substance. Mostly these ‘special substances’ are amino acids like glycine and taurine, and other substances, like glutathione, sulfate, and methyl. Each conveyor belt adds/conjugates a specific substance.

The seven parts (conveyor belts) of the phase 2 system are called:
The Glycine pathway
The Taurine pathway
The Glutathione pathway
The Sulphation (sulfation) pathway
The Methylation pathway
The Glucoronidation pathway
The Acetylation pathway

You need to supply the ‘special conjugation substances’ via your diet or the production lines come to a halt. If one conveyor belt stops because it is missing its ‘special substance’, the other conveyor belts are equipped to deal with some of these jammed items that need conjugation. But certain compounds are restricted to only go down a specific pathway and production must wait until more of the ‘special substance’ is provided. Even still, phase 1 does not stop production and it just keeps on going.

Since many of these ‘special substances’ can be derived from big proteins that you eat, it shows why regular protein meals are vital for ill people. Sometimes your body is unable to go through all of the specific steps it needs to, in order to break complex proteins down fully and thereby provide phase 2 some of the seven particular ‘special substances’. For example, sulphur (sulfur foods) are metabolized down through several steps in order to produce sulphate (sulfate), but some people are unable to complete the conversion of sulphur into sulphate, or they do it poorly, due to faulty or poisoned enzymes. In order to keep the Sulphation pathway moving, they must supply sulphate to the body via supplements taken on a daily basis, such as Magnesium sulphate ( Epsom Salts ) or Glucosamine sulphate. Different people will have different problems with different pathways.

You can think of the toxic metabolites from phase 1 as many freshly laid and fragile eggs from different birds that are churned out every second in the phase 1 factory. These eggs need to be quickly organised and sent down the correct conveyor belt or they will back-up and create a huge mess. Chicken eggs must go down the chicken egg conveyor belt, and geese eggs down the geese egg conveyor belt. So the eggs are swiftly organized onto specific conveyor phase 2 belts where workers (phase 2 enzymes) add certain ‘special substances’, to create boxes and bubble wrap (taurine, glycine,sulphate) which stabilizes them and makes them ready for transport.

In Multiple Chemical Sensitivity (MCS) the phase 1 birds are making way to many eggs, while the phase 2 workers are overwhelmed and can’t keep up with the packing. This creates a bottle-neck at the beginning of the phase 2 conveyor belt and the eggs spill over and make a huge mess. When this happens in the body, the toxic metabolites that are bottle-necked at the beginning of phase 2 start to circulate and cause a lot of damage throughout the system. So when a person with MCS encounters certain compounds like perfumes or paint that need to be detoxified by the phase 2 system and it is not working, then they get a lot of symptoms. These individuals need help to slow down phase 1 pathways, with phase 1 inhibitors such as niacinamide (500-1000mg/day) or grapefruit juice (250ml 3-4 times per day) or oregano oil, this also kills intestinal yeast and dosages vary) and support/speed up phase 2 pathways (e.g. with substances like sulphate or methyl groups).

Grapefruit juice and curcumin (in tumeric, though people with high plasma cysteine and sulfur problems are cautioned by Andy Cutler, in Amalgam Illness, as curcumin raises plasma cysteine further ) are able to accomplish both of these tasks by slowing down phase 1 and speeding up phase 2 simultaneously. Here is a chart that shows the substances metabolised in the phase 1 pathways, and inducers and inhibitors of the specific enzymes.It takes quite a bit of personal experimentation to find out where exactly in your liver pathways you are having trouble.



Lab tests

Some labs such as Genova Labs (they used to be known as Great Smokies Lab) used to test the ability of the liver to detoxify substances through its pathways, through their Liver Detoxification Profile, which assessed the pathways by challenging them with specific substances, such as caffeine for the phase 1 pathway. However, since this form of challenge testing only focused on one of the phase 1 enzyme, its clinical significance was of lessor value. It is no longer available and has since been replaced by the DetoxiGenomic® Profile test, which is much more comprehensive in the sense that it looks at your DNA and check for the presence or absence of certain SNP’s, which are simply areas of your DNA which code for how you detoxify substances.

Genova says this test, “evaluates SNPs associated with increased risk of impaired detoxification capacity especially when exposed to environmental toxins. It also identifies individuals potentially susceptible to adverse drug reactions.” The value of this test is that you only ever have to do it once in your life, as genes do not change. The benefits of its clinical application at this stage are still unknown to us, and we shall report back once we know more.



In USA: Genova Labs for the DetoxiGenomic Profile test.
In Europe & the UK: Contact Genova Europe
In South Africa: Pathcare will be starting an association with Genova Labs towards the end of 2010, whereby some Genova tests will become available. We will let you know when this occurs.
There is a more comprehensive article on the liver pathways here… It is well worth reading.



So where do I start?
One of the most important principles of detoxification is that you need to clean your bowels first and replenish its normal ecology through the eradication of pathogens and the reintroduction of good bacteria through pro-biotics. The phrase: “You need to clean downstream before you can clean upstream”, implied that you should clean your bowels first, otherwise you will be sending dirty water from the gut to a clean chemical plant at the liver! This is a common cause for so called detoxification-illness.

Practically that means assess the ecology of the bowels with a stool test. Thereafter follow these common gut-cleaning principles:

First, Weed (remove offending foods and pathogens), then
Seed (take appropriate pro-biotics), and thereafter
Feed (eat the correct foods for your body).

Many people will have developed a leaky gut by the time they are ill, and so often the gut lining needs to be repaired during the initial weeding phase by using certain products containing glutamine, DLG (DeGlycerized Licorice so as to remove the cortisol retaining properties) and aloe (with the laxative properties removed). An example of a good product that can achieve this is Glutagenics by Metagenics.

Make sure you get your gut health better before taking compounds to assist your liver pathways. This is a vital step not to miss out!

Another vital consideration before beginning a detoxification program is to ensure that your metabolism is up to the task, by addressing your adrenals and thyroid. Your body temperature indicates just how well your adrenal and thyroid hormones are having an effect at a receptor level. You need your daily average (based on three oral temperatures taken around 9am, 12noon and 3pm) to measure 98.6 degrees F/37 degrees C and stable for good health. If they are higher one day and lower the next, it indicates adrenal problems – because the adrenals control the stability of internal temperature. If they are low but stable, it indicates thyroid problems – because the thyroid hormones (T3 in specific) lift the temperature. Saliva testing of the adrenals by DiagnosTechs Labs, and temperature testing and thyroid blood tests, will help you figure out if these glands are making sufficient adrenal and thyroid hormones to keep you healthy.

The thyroid labs will measure the glandular output (how much hormone is been secreted by the glands in the blood), while temperatures will measure the effectiveness of the hormones at a receptor level i.e. are they actually doing what they are supposed to.

To summarise:

Tackle your gut first. Get a stool test and use pro-biotics, diet, and supplements to heal the gut lining.
Look into your hormonal system. Important: work on your adrenals first, and thereafter look towards your thyroid, via thyroid support, in order to begin moving your body temperature, closer towards 37 degrees C (98.6F) and towards stability.
Address your liver pathways if necessary (as above), and:
Continue down your detoxification path to remove offending metals e.g with oral chelation.


http://livingnetwork.co.za/chelationnetwork/food/liver-detox-pathways/