How do our inherited genetics impact our detoxification processes? It seems they impact a lot, but take heart, because good nutrition can actually override them! This is the art of Nutritional Genomics. It is the area of study focused on looking at how our diet, and the nutrients we absorb from food, interact and act on our inherited genes. The exciting news is that what we eat can have a major influence on rectifying the functional genes we have inherited that are involved in the biochemical pathways in our bodies (a.k.a our engine rooms).
Genetics and their Impacts on our Detoxification
How do our genes and the functioning enzymes they create, influence how well our liver detoxifies toxins? The genes show what our POTENTIAL strengths and weaknesses might be with liver detoxification. Potential genetic weaknesses can be strengthened with good lifestyle choices and good nutrition, and conversely potential genetic strengths can be weakened with poor lifestyle choices and poor nutrition.
Let's break down what happens in the liver detoxification process, and where the genes and the enzymes they code for, are located, and what they do.
Graphic from MTHFRSupport Variant Report v2.12
Toxins that enter our body can be endogenous (we produce them) or exogenous (from outside the body). Most toxins are fat soluble meaning they will get stored in our fat cells if we aren't clearing them out of our body properly. If we aren't clearing them well, they can be released at times of stress (even released when we lose weight) and do damage to us if our detoxification pathways aren't clear. Let's explore the detoxification process in the liver and where our genes interact in the process.
Phase I Detoxification known as Oxidation
Shown on the left hand side of the graphic above.
The Cytochrome P450 enzymes (CYP enzymes) are used to convert toxins and hormones we make (oestrogen, testosterone, cholesterol etc) into smaller, more water soluble components. This process results in intermediary free radicals which are reactive (they can do damage). Phase I is important to be able to make the toxins in a form that can be excreted by the body, but if we don't have good Phase II pathway processes, or Phase III (which is pooping the products out), then our body sits with these reactive products in our liver that can cause damage. This is the reason why constipation is not a good thing as it allows the toxic waste to hand around in our bodies. As a protective safeguard against this, we need to eat lots of antioxidants in the form of colourful fruits and vegetables, nuts and seeds, herbs and spices.
Phase I detoxification is primarily for removing medications, drugs, and hormones.
We favourably stimulate Phase I activity by consuming cruciferous vegetables (broccoli, cauliflower, Brussel sprouts, watercress, cabbage, kale), foods rich in B vitamins (organic, grass fed meat, wild caught salmon), folate (green leafy vegetables like spinach, beet greens, rocket, turnip, lentils), colourful vegetables for flavonoids, vitamin C rich foods (strawberries, capsicum, oranges, lemons) and glutathione promoting foods from sulphur rich foods (like garlic, onions), herbs (e.g. Milk Thistle).
We can overstimulate Phase I activity (which isn't desired) with caffeine, alcohol, exposure to paint fumes, pesticides, oral contraceptive pill, cortisone, heavy metals (amalgam fillings), pesticides, steroids, lipopolysaaccharides (bacterial toxins from inflammatory, saturated fat diets), mycotoxins (from mould), pthalates and BPA (from plastics), dioxins (from industrial waste) etc. This mean we can generate more reactive products from these. This can lead to health issues like cancer, cardiovascular problems, premature ageing, skin damage etc.
As Phase I makes toxins more reactive, you can start to see why our life choices can have a negative impact on our liver. Phase II detoxification is crucial in ensuring this doesn't happen.
Some examples of CYP enzymes used in Phase I detoxification are:
CYP1A1 and CYP1B1 metabolise oestrogen
CYP1A2 is involved in caffeine metabolism. If you are one of these people that can't drink coffee after a certain time as it keeps you awake then you may be a slow metaboliser based on your CYP1A2 gene expression.
CYP19A1 metabolises androgens (testosterone)
CYP3A4 metabolises most of our pharmaceutical medications. Inflammation slows down our CYP3A4 activity. If we are taking pharmaceutical medications, we need to make sure we aren't inflamed. This often isn't the case, as it is often the reason we are on medication in the first place.
Drugs in our bodies can be up or down regulated depending on our genes.
Inflammation can either up-regulate or down-regulate activity also.
Phase II Detoxification known as Conjugation
Shown on the right side of the graphic above.
After Phase I has made the toxins more water soluble (good thing) but more reactive (bad thing), we need to grab hold of them to eliminate them from the body. The liver does this via six processes in Phase 2 detoxification. Whilst it is described technically below, we can think of it in simple terms as just adding another chemical (conjugating) to the toxin to help it get eliminated.
Glucuronidation - uses the enzyme UGT to add UDP-glucuronic acid to metabolites for excretion. This pathway is one of the most important pathways. It is important for the metabolism of steroid hormones like oestrogen, androgens (testosterone, DHEA), thyroid hormones (T3, T4), Bilirubin, some mycotoxins, medications (NSAID's, Benzo's, Paracetamol, Codeine, Morphine). Issues that can occur include Gilbert's syndrome if you have impaired UGT enzymes seen when your bilirubin level is high. Also, if we have high levels of the enzyme B-glucuronidase from bacteria in our gut microbiome, then that enzyme will destroy all the good work your body has done in conjugating up the toxins for elimination, by literally 'cutting them up' and will resdispense them throughout your body again. This is a way that we can get increased oestrogen imbalance, and histamine imbalance in our bodies. The message is: eat well (fruits and vegetables) to keep B-glucuronidase levels normal, and to encourage healthy Phase II pathway clearance. A practitioner can help bring this back in balance for you.
Sulphation - uses the SULT gene to make sulfotransferase enzyme that transfers a sulphate group to toxins to make water soluble for excretion. Our body requires sulphur rich foods (cruciferous vegetables, allium vegetables, eggs, organic, grass fed meats), and epsom salt baths to help with this process. Issues can occur if we have low protein diets, low sulphur food diets, low magnesium levels, issues with our SULT (sulphotransferase enzymes), have very high toxin exposure which can deplete sulphur from our bodies, have inflammation, or gut dysbiosis. Signs you may have sulphating issues are chemical sensitivities, asthma, chronic fatigue, migraines and more. A practitioner can help bring this back in balance for you.
Methylation - uses methyl transferases with the methyl group (-CH3) being one of the most powerful groups that gets transferred in many processes in our body to keep us healthy, including looking after our DNA. Methylation is involved in many bodily processes, as well as detoxification. The MTHFR gene expression can have an impact on the amount of methyl donors generated. If you are homozygous you have a very limited amount of methyl donors generated so you have to work really hard on your diet to make them. This means eating a lot of green, leafy vegetables. Methylation is involved in the detoxification of oestrogen in the liver. Phase II methylation of oestrogen is governed by our COMT enzyme (catechol-o-methyltransferase) which relies on its methyl donor from SAM (S-adenyosylmethionine). We need methionine, choline, B12 and folate for this to function well. Methylation conjugates oestrogen, catecholamines (dopamine, adrenalin etc), histamine, heavy metals, phenols, and aromatic amines (smells and fumes). Inhibitors of methylation are the oral contraceptive pill, antibiotics, and proton pump inhibitors that are taken for gastric reflux. If methylation isn't occurring well we can get elevated homocysteine which is said to be a predictor for cardiac health issues. A low homocysteine on the other hand can be a sign of oxidative stress, which results in less ability to make glutathione which is our body's most powerful antioxidant. Homocysteine is the 'canary in the mine' and is an important blood test to monitor and results should be around 7-7.5 umol/L. We need good amounts of active folate, active Vitamin B12, methionine, active Vitamin B6, and Zinc to make this pathway work well. A practitioner can help bring this back in balance for you.
Glutathione conjugation - process uses Glutathione s-transferase (GST) and crucially relies on glutathione which is the body's major antioxidant. Many chronic illnesses are associated with glutathione deficiency. It processes pesticides, herbicides, heavy metals, mycotoxins, medications, and alcohol. N-acetyl cysteine is the precursor to glutathione. A qualified practitioner can hep bring this back in balance for you.
Acetylation - requires NAT and NAT2 (N-acetyl transferases) and is used for medication and drug detoxification, histamine and aromatic amines. Unlike other enzymes activity in the other Phase 2 processes that are affected by environmental factors, acetylation is mostly genetically determined to work well or not.
Amino acid conjugation - used for salicylate conjugation (from our salicylate foods, and also aspirin, NSAID's), and in personal care products, with preservatives in our foods, and toluene in nail polish, glues, cleaning products etc. A practitioner can help bring this back in balance for you.
Phase III Detoxification known as Transportation
Phase III is the transport of the conjugated toxins to the kidneys for elimination in urine, or added to bile and excreted from our bowels as faeces (poop).
Phase III requires adequate hydration (2-2.5L water per day), fibre, and ensuring your daily poop looks like a 4 or 5 score on the Bristol Stool Chart - like a firm, slippery banana! Naturopaths are comfortable discussing poop.
If you are not scoring a 3 or 4 then it is likely you have dysbiosis (an unhealthy 'playground' of bacteria in your bowels), or are lacking in fibre (which is the food of choice for the good bacteria we want in our bowels), are magnesium deficient, have some sort of food intolerance, or simply don't drink enough water.
IMPORTANT NOTE:
Hopefully through reading this you can see that you must have good elimination occurring before you start a liver detoxification program. If you aren't clearing the toxic waste from your body that the liver has processed, you can only become more toxic if you aren't pooping, urinating well, and sweating. Never work on Phase I detoxification without working on ensuring Phase II works optimally. The order should always be to focus on Phase III (daily pooping), then Phase II and the Phase I.
Alcohol - interesting note
Alcohol stimulates Phase I and slows down Phase II detoxification. This means there is an increase of the reactive oxygen species (ROS) that our body won't allow to hang around in our blood so it stores it in fat cells (fatty liver). We can start to see how alcohol can cause fatty liver disease, destroy liver cells and be quite toxic for us. Moderation is the key.
Cholesterol - interesting note
If your Phase 2 detoxification isn't working well, you can get elevated cholesterol. It is a sign that the liver needs some attention. Cholesterol is needed to make sex hormones and for brain cognition, so just the correct amount is needed. A confounder for high cholesterol, is that essential fatty acids (EFA's) and zinc are needed to convert cholesterol to sex hormones. If we are deficient in EFA's (from fish, nuts and seeds) and zinc (oysters are a great source) we can't convert, and so our cholesterol levels remain high.
Putting it all together graphically again, we see the complete liver detoxification process, and the nutrients required to make it work well.
A detoxification program or liver support program should be undertaken with a practitioner to safeguard against potential issues. A practitioner can share the specific knowledge you need to take care of your personal circumstances.
The old saying 'we are what we eat' can be translated to 'we are what we don't detoxify'.
If you feel you would like to discuss your own needs in this regard, or wish to have genetic profiling for your wellness potential tested and interpreted for you, please feel free to book an appointment.
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References:
Hodges R & Minich D, (2015), Modulation of Metabolic Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application, J Nutrition Metabolism doi:10.1155/2015/760689
Mini D & Brown B, (2019), A Review of Dietary (Phyto) Nutrients for Glutathione Support, Nutrients, doi:10.3390/nu11092073
Conners K, (2022), The 7 Phases of Detoxification
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