Phase I Detoxification Flashcards
Detoxification
The process of transforming fat-soluble toxins and xenobiotics into water-soluble compounds that can be eliminated via the urine or bile:
* Detoxification is carried out by a variety of cells, but takes place primarily in hepatocytes (functional liver cells).
Toxicant / xenobiotic
Foreign substances (typically synthetic) found in the body that are not derived from a normal diet or produced endogenously e.g., pesticides, food additives, heavy metals, pharmaceutical drugs, industrial chemicals.
Endogenous toxins
Produced in the body
*GI microbes:
‒Toxic compounds such as aldehydes, alcohols and indoles released from undesirable bacteria and fungi.
‒Fragments of dysbiotic bacteria called lipopolysaccharides (endotoxins) (LPS) can enter the bloodstream (esp. if ↑ intestinal permeability) causing excessive immune reactions.
* Waste products from normal metabolic processes e.g., ureaif not properly metabolised in the liver.
* Poorly detoxified / eliminated hormones (e.g., chronic constipation can lead to poor oestrogen elimination).
Antioxidants
Play a central role in detoxification by converting free radicals / ROS to stable, non-toxic molecules. They can be divided into three main groups:
- Antioxidant enzymes.
- Chain-breaking antioxidants ―the chain of ROS can be broken when a molecule can accept or donate an electron without needing to rectify its gain or loss.
- Transition metal-binding proteins.
Phase Zero
The entry of the toxin into the cell (primarily hepatocytes) or exit of the unmetabolised toxin from storage inside cells such as adipocytes:
* Fat-soluble toxins diffuse through the cell membrane.
* Water-soluble or charged toxins need to access or leave the cell through a transporter.The main transporter families used for phase zero are (both with many different transporters):
– Solute carriers(SLC) and ATP binding cassette carriers.
Phase I
Primarily involves transformation enzymes collectively known as cytochrome P450 (CYP450) in the liver:
* Most toxins that arrive inside the hepatocytes are lipophilic and have to undergo phase I detoxification.
* The CYP450 + toxin / hormone reaction creates an active binding site on the toxin (often exposing an –OH / alcohol group). This makes them morewater-soluble, but also more reactive in order for conjugation to occur (phase II).
* Therefore, in phase I, intermediates are formed which are very bioactive.
CYP450
Involves 50 to 100 enzymes, each of which is best able to detoxify certain compounds, but has broad specificity:
* This means the liver can accommodate a wide range of chemical exposure. However:
‒ Many of the enzymes are produced in response to increased exposure to a certain toxin by producing more of the enzyme that degrades it. This can happen at the expense of other toxin biotransformation.
‒ Induction of phase I enzymes without co-induction of phase II can =increased reactive intermediates, ↑ oxidative stress.
Phase I to phase II key considerations
- The progression of metabolites from phase I through to phase II must happen in quick succession to minimise damaging effects of intermediary products.
- Genetic variations (SNPs), diet and availability of nutrient co-factors can influence an individual’s ability to metabolise toxins.
- Phase II enzymes are generally less inducible than phase I.
- Typically, phase I will be upregulated due to toxic load, while phase II will be slow due to overwhelm from heightened phase I activity and / or lack of co-factors (e.g., a poor, nutrient-depleted diet).
Supporting phase I detoxification
Reduce the toxic load to slow phase I:
1. Go organic to minimise intake of pesticides and other xenobiotics from the food chain.
2. Minimise exposure of xenobiotics in toiletries and household products.
3. Stop smoking and avoid caffeine.
4. Avoid chargrilled and smoked foods.
5. Reduce or ideally eliminate alcohol.
6. Avoid unnecessary medications.
7. Avoid use of plastics in contact with food.
Phase I detoxification co-factors
- The B complex vitamins are vital co-factors for the action of the cytochrome P450 enzymes and other phase I enzyme families.
- Alcohol depletes B vitamins and so should be avoided to optimise an individual’s B vitamin status.
- B vitamin-rich foods include whole grains, legumes, mushrooms, sunflower seeds, pistachios, wild fish, eggs, sea vegetables.
- Adequate amounts of the branched chain amino acids (BCAAs) leucine, isoleucine and valine are also necessary to support phase I activity. Sources include quinoa, fish, eggs and meat.
CYP450 genes
CYP2E1―ethanol
CYP17A1―pregnenolone
CYP1A2―caffeine
CYP19A1―testosterone
CYP2C9―warfarin
CYP1A1―oestrogen
CYP450 SNPs
CYP1A1 - oestrogen
CYP1A2 - caffeine
CYP1A1
– Deactivating oestrogen. An SNP of this gene increases the risk of oestrogen dominance.
– Detoxifying many toxins including polycyclic aromatic hydrocarbons (PAHs) and solvents.PAHs damage DNA increasing cancer risk. They are formed in chargrilled meat, smoked foods and cigarettes.
- Avoid (more crucial for these people): Chargrilled meats and smoked food. Smoking and exposure to second-hand smoke. Industrial pollutants and synthetic oestrogens (e.g., parabens in beauty products, plastic).
- Focus on plant foods (minimal animal protein), rich in colour (phytonutrients) including polyphenols (green tea, berries, apples, etc.). Also rosemary.
- Sulphur-rich foods, especially cruciferous vegetables (e.g., broccoli sprouts for the high I3C content) and allium vegetables).
- Consider supplementation with Indole-3-carbinol.
CYP1A2
Gene: CYP1A2 gene encodes a member of the CYP450 family of enzymes, which metabolise nutrients and drugs, including caffeine.
* SNP: The SNP at rs762551 impacts CYP1A2 activity.Individuals with the CC genotype, also known as CYP1A2*1C, are ‘slow’ caffeine metabolisers.
‒ Caffeine intake > 300 mg / day can be damaging to the brain, heart, liver and kidneys.
* SNP recommendations:Avoid all caffeine intake from coffee, tea and foods such as chocolate.
