This article discusses the phase I and phase II detoxification and biotransformation pathways and
promotes using food to support these highly complex processes.
Components of this lifestyle include:
- Avoidance of environmental toxicants such as heavy metals, persistent organic pollutants, and electromagnetic radiation
- Mobilisation or elimination of toxicants via loss of excessive fat and use of saunas, chelation therapy, and exercise
- Optimal gastrointestinal health
- Excellent nutrition and hydration
- Attention to stress and resilience and to relational health
- Adequate sleep and relaxation
The below figure shows an important tool that summarises the phase I and phase II detoxification and biotransformation pathways and provides a conceptual framework for clinicians and patients. Toxicants originate from exogenous sources such as drugs (pharmaceutical and recreational); heavy metals; chemicals, such as herbicides, pesticides, insecticides, food additives, household cleaners, and other pollutants; and microbials. Toxicants also originate from endogenous sources, such as bacterial endotoxins and the end products of metabolism. It is important to realise that steroid hormones and fat-soluble vitamins are also metabolised through these pathways.
The phase I system comprises at least 57 pathways known as the cytochrome P450 (CYP) family of mixed-function oxidases. Nine of the most commonly used CYP enzymes are 1A1, 1B1, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4. In phase I, toxicants are transformed to more polar, less lipid-soluble forms through oxidation, reduction, hydrolysis, hydration and dehalogenation reactions.
For the P450 enzymes to be present and conformationally active, an individual must consume high-quality, bioavailable protein as well as a host of phytonutrients, botanicals, minerals, fats, and carbohydrates.
After going through the phase I processes, the activated toxicants are often more toxic than their parent compounds. If these activated, intermediate metabolites are not further metabolized via the phase II conjugation pathways; they can cause cellular damage by covalently binding to various proteins, lipids, and nucleic acids within cells.
Reactive oxygen species are also a by-product of phase I activity. Therefore, to quench the propagation of free-radical activity, adequate protection from antioxidant nutrients is required using a number of plant derivatives, including:
- The carotenes—lycopene, β-carotene, lutein, zeaxanthin, and astaxanthin
- Ascorbic acid (vitamin C)
- Tocopherol (vitamin E)
- Coenzyme Q10
- Thiols, found in garlic, onions, and cruciferous vegetables
- Silymarin (milk thistle)
Other nutrients include:
- N -acetylcysteine
- α-lipoic acid
- Polyphenols such as pomegranates, green tea, and raspberries
- Anthocyanins found in blueberries and blackberries
A useful reminder of our individuality:
Individual differences in drug metabolism and pharmacokinetics contribute to the individual-to-individual variation that characterises the responses to many drugs and other foreign chemicals and presents a major challenge in clinical pharmacology. Individual variation in the expression of major drug-metabolising enzymes (DMEs), including cytochromes P450 (P450s), sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferase, is associated with substantial individual differences in the bioavailability and clearance of drugs and other xenobiotics. Given the crucial role of hepatic DMEs in regulating the pharmacological and biological activity of drugs as well as steroid and other endobiotics, it is important to understand the regulatory features that lead to individual differences in the expression of DMEs. Factors that contribute to inter-individual differences in DME expression and drug metabolism include genetic polymorphisms, prior or concomitant exposure to drugs and environmental chemicals, dietary factors, pregnancy, diseased states, epigenetic factors, and endogenous hormonal factors, which change with age and differ between male and female subjects.
Factors that influence the activity of certain CYP 450 Enzymes:
The below visal highlights some of the key enzymes involved in phase 1 detoxification and what influences their activity. See how inflammation down regulates them? Inflammation, to some level is often found in chronic health conditions including IBS and CFS, among many others.
The Gut-Brain Axis
Many of us have now heard of the gut-brain axis. An interesting paper I found discussed the gut-liver axis. The paper stated:
It is becoming increasingly evident that peripheral organ-centered inflammatory diseases, including chronic inflammatory liver diseases, are associated with changes in central neural transmission that result in alterations in behaviour. These behavioural changes include sickness behaviours, such as fatigue, cognitive dysfunction, mood disorders, and sleep disturbances. While such behaviours have a significant impact on quality of life, the changes within the brain and the communication pathways between the liver and the brain that give rise to changes in central neural activity are not fully understood. Traditionally, neural and humoral communication pathways have been described, with the three cytokines TNF, IL-1, and IL-6 receiving the most attention in mediating communication between the periphery and the brain, in the setting of peripheral inflammation. However, more recently, we described an immune-mediated communication pathway in experimentally induced liver inflammation whereby, in response to activation of resident immune cells in the brain (i.e., the microglia), peripheral circulating monocytes transmigrate into the brain, leading to development of sickness behaviours. These signalling pathways drive changes in behaviour by altering central neurotransmitter systems. Specifically, changes in serotonergic and corticotropin-releasing hormone neurotransmission have been demonstrated and implicated in liver inflammation-associated sickness behaviours. Understanding how the liver communicates with the brain in the setting of chronic inflammatory liver diseases will help delineate novel therapeutic targets that can reduce the burden of symptoms in patients with liver disease.
The Gut-Liver Axis
In a paper published in the World Journal of Gastroenterology the authors discussed the gut-liver axis. Essentially there is a relationship between the health of our digestive system and the health of our liver.
Gut flora and bacterial translocation (BT, aka leaky gut) play important roles in the pathogenesis of chronic liver disease, including cirrhosis and its complications. Intestinal bacterial overgrowth and increased bacterial translocation of gut flora from the intestinal lumen predispose patients to bacterial infections, major complications and also play a role in the pathogenesis of chronic liver disorders. Levels of bacterial lipopolysaccharide, a component of gram-negative bacteria, are increased in the portal and/or systemic circulation in several types of chronic liver disease. Impaired gut epithelial integrity due to alterations in tight junction proteins may be the pathological mechanism underlying bacterial translocation. Preclinical and clinical studies over the last decade have suggested a role for bacterial translocation in the pathogenesis of nonalcoholic steatohepatitis (NASH). Bacterial overgrowth, immune dysfunction, alteration of the luminal factors, and altered intestinal permeability are all involved in the pathogenesis of NASH and its complications. A better understanding of the cell-specific recognition and intracellular signaling events involved in sensing gut-derived microbes will help in the development of means to achieve an optimal balance in the gut-liver axis and ameliorate liver diseases.
I often recommend a stool test, a hydrogen breath test or/and a leaky gut test when clients come to me with conditions such as cirrhosis or fatty liver.
As you can, detoxification isn’t always a simple process. While we want to ensure our diet is one that is healthy and includes a diverse range of nutrients, including those listed above, in states of poor health we may need to consider supporting these pathways. Or at the very least, ensuring our clients understand that some of there symptoms may be caused by sub-optimal detox pathways, and thus, as their digestive health improves (as an example) their liver health/function will likely improve also.
I am a great example here. When my IBS was at is’s worst I seemed to be very reactive to my environment. I would sneeze and get bunged up when exposed to deodorants or perfumes as well as cleaning products. I would have a sneezing fit walking down the isle in the supermarket where cleaning products were stored! Interestingly, at a genetic level, I am not the best phase two detoxifier (notice all the red in phase two below!). So this makes sense. When I had bacterial and fungal overgrowths in my digestive system, and leaky gut, I put additional strain on my liver and it was likely struggling to cope.
This means I need to be mindful of supporting digestive health (as this influences liver health) and I need to support phase two pathways by including foods listed above.
As you can see, we can go in to a lot of detail with these pathways and processes. It isn’t always necessary and often by personalising the diet around testing, such as a stool and breath test to investigate gut heath, considerable improvement can be experienced.
If you have any questions don’t get hesitate to get in touch and if you are interested in learning about yourself, at this level, then we can organise a time to chat.