2b. Detoxification Flashcards
What is detoxification?
Process of transforming fat-soluble toxins into water-soluble compounds that can be eliminated via urine or bile
In which cells does detoxification primarily take place?
Hepatocytes
How can detoxification be supported in clinic?
Minimise toxic load
Support detoxification pathways
Support elimination pathways
What are xenobiotic toxins?
Foreign substances found in the body that are not derived from a normal diet or produced endogenously e.g. pesticides, food additives, heavy metals, medications, industrial chemicals
Examples of endogenous toxins
GI microbes/dysbiotic bacteria
Waste products from normal metabolic processes e.g. urea from ammonia
Poorly detoxified/eliminated hormones e.g. chronic constipation = reduced oestrogen elimination
Examples of exogenous chemical toxins
BPA
Pesticides
Phthalates
PBDEs
PAHs
Solvents
Sources of BPA
Food tins
Plastic packaging
What conditions can poor BPA detoxification/elimination be associated with?
T2D
Infertility
Oestrogen disruption
Source of pesticides
Crops
Water contamination
What conditions can poor pesticide detoxification/elimination be associated with?
AZD
Infertility/erectile dysfunction
RA
SLE
Cancer
Sources of phthalates
Plastics
Beauty products
What conditions can poor phthalate detoxification/elimination be associated with?
T2D
Infertility
Allergies
Sources of PBDEs
Flame retardants
Farmed fish
What conditions can poor PBDE detoxification/elimination be associated with?
Insulin resistance
Child behavioural problems
Sources of PAHs
Air pollution/vehicle exhausts
What conditions can poor PAH detoxification/elimination be associated with?
COPD
T2D
ADHD
AZD
Atopic conditions
Sources of solvents
Vehicle exhausts
Smoking
Foods
What conditions can poor solvent detoxification/elimination be associated with?
AZD
Infertility
MS
RA
Autism
Examples of exogenous metal toxins
Aluminium
Mercury
Arsenic
Sources of aluminium
Foil
Anti-perspirants
Vaccines
What conditions can poor aluminium detoxification/elimination be associated with?
AZD
Mitochondrial damage
Sources of mercury
Amalgams
Fish (esp larger)
Water
Vaccines
Air pollution
What conditions can poor mercury detoxification/elimination be associated with?
Chronic fatigue
Neurological damage
Hashimoto’s
ADHD
Infertility
SLE
Sources of arsenic
Water
Rice
Chicken
What conditions can poor arsenic detoxification/elimination be associated with?
T2D
Gout
Cancer
Peripheral neuropathy
Methods for reducing toxins in life
Eat organic
Avoid farmed/large fish
Avoid plastic packaging
Avoid non-stick pans
Air purifier
Water filter
Non-chemical ridden beauty, cleaning products
Avoid alcohol, smoking, drugs
Signs/symptoms of sluggish/sad liver
Poor appetite
Fatigue
Nausea esp in morning
Difficulty digesting fatty foods
Alcohol intolerance
Dry skin/itching
Waking between 1am and 3am
Headaches
Dark circles under eyes
Yellowing of whites of eyes
Yellow coating on tongue
Methods of testing for toxins
Hair analysis - toxins
Urine - heavy metals
Blood - heavy metals
Stool analysis
Genetic profiling
Why are AOs crucial following P1 detoxification?
P1 generates free radicals
AOs help to avoid tissue damage by converting free radicals to non-toxic molecules
What are the 3 main groups of AOs?
AO enzymes
Chain breaking AOs (enhances stability of oxidation)
Transition metal-binding proteins
Examples of AO enzymes
Superoxide dismutase (SOD)
Catalase
Glutathione peroxidase
Glutathione reductase
What do superoxide dismutase enzymes do?
Convert superoxide to hydrogen peroxide
(hydrogen peroxide is then detoxified by catalase or glutathione peroxidase)
Nutrients needed for superoxide dismutase enzymes to work
Zn
Cu
Mn
What do catalase enzymes and glutathione peroxidase do?
Convert hydrogen peroxide to H2O and O2
Nutrient needed for catalase enzymes to work
Fe
Nutrient needed for glutathione peroxidase enzymes to work
Se
What do glutathione reductase enzymes do?
Regenerates glutathione that has been oxidised
Nutrient needed for glutathione reductase enzymes to work
B3
Examples of chain-breaking AOs
C
E
Flavonoids
Carotenoids
Food sources of vit E
Sunflower seeds
Almonds
OO
Avocado
Sweet potato
Food sources of flavonoids
Quercetin - red apples, red onion
Anthocyanins - red grapes
Catechins - green tea
Kaempferol - kale, spinach
Food sources of carotenoids
Yellow, orange, red fruits and veg
Green veg
Example of transition metal AOs
Metallothionein (MT)
What do metallothioneins do?
Bind to essential and toxic heavy metals
Reduce oxidative stress
Nutrients needed for metallothionein AOs
Cysteine (legumes, sunflower seeds, eggs, chicken)
Zn
Cu
Se
What is P0 of detoxification?
Entry of the toxin into the cell
Exit of the unmetabolised toxin from storage inside cells e.g. adipocytes
How do fat soluble toxins leave the cell?
Via diffusion
How do water soluble toxins leave the cell?
Via a transporter
Examples of water soluble toxin transporters
Solute carriers
ATP binding cassette carriers
What happens during P1 detoxification?
Transformation enzymes (CYP450) and a toxin/hormone reaction creates an active binding site on the toxin
This makes the toxin more water soluble but also more reactive
How many CYP450 enzymes are there?
50 - 100
Does each CYP450 enzyme detoxify a specific compound or are they broad?
Specifity
How does increased exposure to one toxin affect the CYP450 enzymes?
Each enzyme is produced in response to exposure to a certain toxin
Increased exposure to a toxin increases the amount of that enzyme to degrade it
This can happen at the expense of other enzymes and toxin biotransformation/ degradation
What can increase P1 activity?
Toxic load through:
Smoking
Alcohol
Caffeine
Chargrilled food
Why must the progression of P1 to P2 happen quickly?
To minimise the damaging effects of intermediary products
What can affect an individual’s ability to metabolise toxins in P1?
SNPs
Diet
Availability of nutrient co-factors
Why will P2 be slowed down if P1 is upregulated?
Due to overwhelm
Lack of dietary co-factors
How to support P1 detoxification
Go organic to minimise exposure to pesticides
Minimise exposure to xenobiotics in toiletries and household products
Stop smoking
Avoid caffeine
Avoid chargrilled/smoked foods
Reduce or ideally eliminate alcohol
Avoid unnecessary medications
Avoid use of plastics in contact with food
Dietary co-factors to support P1 detoxification
B vits (action of CYP450 enzymes
BCAAs - leucine, isoleucine, valine
Food sources of B vits
Whole grains
Legumes
Mushrooms
Sunflower seeds
Eggs
Fish
Food sources of leucine, isoleucine and valine
Quinoa
Fish
Eggs
Meat
What do SNPs on genes have the potential to do during detoxification?
Increase toxicity by speeding up conversion of compounds to reactive intermediary products
Cause an accumulation of unmetabolised toxins
What do CYP1A2 enzymes metabolise?
Caffeine
What impact does a SNP on CYP1A2 have on caffeine metabolism?
Slows it down
What do CYP1A1 enzymes do?
Deactivate oestrogen
Detoxifies PAHs and solvents
What impact does a SNP on CYP1A1 have?
Increases risk of oestrogen dominance
PAHs damage DNA - increasing cancer risk
How can a SNP on CYP1A1 be supported?
Avoid chargrilled meat/smoked food
Avoid smoking
Avoid exposure to industrial pollutants and synthetic oestrogens
Focus on plant foods - rainbow, green tea, apples, berries
Su rich foods - cruciferous, broccoli sprouts (I3C) and alliums
What happens during P2 detoxification?
A variety of chemical reactions occur to the reactive toxins to make them safe to be released into the blood or bile for excretion via kidneys or bowel
What are the 6 pathways of P2 detoxification?
Glucuronidation
Sulphation
Glutathione conjugation
Amino acid conjugation
Acethylation
Methylation
What enzyme is involved in glucuronidation?
UDP-glucuronosyltransferases
What happens during glucuronidation?
Glucuronic acid is added to the P1 metabolite
Food sources of glucuronic acid
Apples
Broccoli
Alfalfa
What are detoxified during glucuronidation?
Oestrogens
NSAIDs
Morphine
What is glucuronidation inhibited by?
Aspirin
Smoking
OCP
Fluoride
Foods to support glucuronidation
Citrus peel
Brassica veg
Turmeric
What enzyme is involved in sulphation?
SULT
What happens during sulphation?
Sulphate is added to the P1 metabolite
Food sources of sulphur
Brassicas
Onion
Garlic
Cruciferous
What are detoxified during sulphation?
Steroid hormones
Food additives
Industrial chemicals
What is sulphation inhibited by?
NSAIDs
Tartrazine
What enzyme is involved in acetylation?
NAT
What happens during acetylation?
An acetyl group is added to the P1 metabolite
What are detoxified during acetylation?
Smoke
Histamine
What is acetylation inhibited by?
B and C deficiency
What is acetylation enhanced by?
B1, 5
C
Butyric acid
What enzymes are involved in methylation?
COMT
PEMT
(ones ending in MT)
What happens during methylation?
A methyl group is added to the P1 metabolite
What are detoxified during methylation?
Steroid hormones
Dopamine
Adrenaline
Arsenic
What inhibits methylation?
B12 deficiency
B9 (folate) deficiency
High sucrose diet
Which nutrients enhance methylation?
Methionine
Betaine
Choline
B2, 6, 9, 12
Folate
Mg
What enzyme is involved in glutathione conjugation?
GST
What happens during glutathione conjugation?
Reactive P1 metabolises are reacted with glutathione
What is detoxified during glutathione conjugation?
Xenobiotics
Paracetamol
Heavy metals
What is glutathione conjugation inhibited by?
Deficiencies in:
Se
B6
Zn
Glutathione
What enhances glutathione conjugation?
Brassicas
Turmeric
Citrus peel
Alpha lipoic acid
What enzyme is involved in amino acid conjugation?
Amino acid transferases
What happens during amino acid conjugation?
An amino acid (mostly glycine) is added to the P1 metabolite
What is detoxified during amino acid conjugation?
Xenobiotics
Drugs
What is amino acid conjugation inhibited by?
Low protein diet
What is amino acid conjugation enhanced by?
Glycine - legumes, seaweed, cauliflower, meat, fish, eggs
Taurine
Glutamine
Arginine
What is Nrf2?
A transcription factor key to regulating the body’s detoxification and AO system
What does Nrf2 do?
Increases endogenous AOs to protect against reactive intermediates
Promotes P2 pathways
Which conditions is Nrf2 considered protective against?
Cancer
Kidney dysfunction
CV disease
Neurological disease
Which foods regulate Nrf2 activity?
Phytonutrients - curcumin, broccoli, garlic, epicatechins, lycopene, resveratrol, isoflavones, rosemary, pomegranate, naringenin
What is glutathione’s role in P1 and P2?
P1 - protects against reactive metabolites
P2 - essential compound for glutathione conjugation
What are glutathione’s other roles apart from P1 and P2?
Mitochondrial protection
Bind and transports mercury out of cells and the brain across the BBB
Which amino acid is essential for glutathione synthesis?
Cysteine
Food sources of cysteine
Legumes
Eggs
Sunflower seeds
Which conditions have low levels of glutathione be associated with?
AI
CV disease
Liver diseases
Pulmonary diseases
Neurodegenerative disease
How can glutathione levels be increased?
Decrease depletion (by reducing oxidative stress)
Decrease toxic load
Optimise melatonin
Alpha lipoic acid
Milk thistle
NAC
Resveratrol
Cruciferous veg
Cordyceps
What role does the GSTM1 gene have?
Responsible for the removal of xenobiotics, carcinogens and products of oxidative stress
What can a SNP on the GSTM1 gene lead to?
Reduced capacity for liver detoxification (esp P2)
How can a SNP on the GSTM1 gene be supported?
Minimise toxic load
Increase AOs (eat the rainbow)
Increase cruciferous veg (for the sulforaphane) and alliums
Milk thistle
NAC
Alpha lipoic acid
Se
What happens during P3 detoxification?
Removal and excretion
Detoxified products are pumped into blood or bile for elimination
What sort of proteins are involved in P3?
Antiporter
How can P3 be induced?
Fasting
Good hydration
How can fasting induce P3
Being in a lipolytic state allows toxins stored in fat cells to be mobilised and eliminated
What can inhibit P3?
High doses of isolated phytonutrients
Curcumin
Epicatechins
Which herbs can support bile production and flow?
Dandelion root
Globe artichoke
Burdock root (flow only)
What 2 factors can influence the efficiency of excretion?
Diet
Microflora
How can diet influence excretion?
Fibre binds conjugated xenobiotics
Decreases stool transit time
Reduces amount of deconjugating enzymes in the stool
How can microflora influence excretion?
Dysbiosis can produce enzymes such as beta-glucuronidase that deconjugate P2 compounds and reduce elimination
Deconjugated xenobiotics re-enter the blood and are sent back to the liver for processing
How does milk thistle protect the liver?
Strong AO properties
Protects liver from P1 metabolites
Examples of conditions where milk thistle could be useful
High alcohol intake
Medications
Hepatitis
Which medicinal mushrooms are hepatoprotective?
Shiitake
Maitake
Cordyceps
What are the key genes for metabolising oestrogen?
CYP1A1
CYP1B1
COMT
Why is the CYP1A1 gene important in oestrogen metabolism?
Converts oestrogen into 2OH oestrogens which are neutral or beneficial to the body
Why is the CYP1B1 gene important in oestrogen metabolism?
Converts oestrogen into 4OH oestrogens
Can promote the synthesis of harmful molecules (quinones) which damage DNA and potentially initiate cancer
Why is the COMT gene important in oestrogen metabolism?
Methylation of 2OH and 4OH before detoxification of these oestrogens occur
Which detoxification pathways are involved in the elimination of oestrogen?
Sulphation
Glucuronidation
SNPs on which genes increase the risk of hormone-related cancers?
SULT
UGT
What happens when oestrogen enters the bowel?
Certain gut bacteria deconjugate it, allowing for recirculation via beta-glucuronidase enzymes
What can raised beta-glucuronidase be due to?
Overgrowth of bacteria e.g. E. coli, Clostridium perfringens
How can raised beta-glucuronidase due to bacterial overgrowth be supported?
Mung bean sprouts
Orange peel (infused tea)
Apples
Broccoli
Calcium D-glucarate
Food sources to optimise oestrogen metabolism
Cruciferous veg
Broccoli sprouts (I3C content)
Fibre
Fruit/veg
Water
What should be avoided to optimise oestrogen metabolism?
Dairy
Excess alcohol/caffeine
Water from plastic bottles
Anti-perspirants
Hormonal contraceptives
Non-organic meat/eggs
In what ways can bowel elimination be supported?
Hydration
Fibre
Mucilaginous foods
Eradicate pathogens
Repopulate microflora
Support intestinal mucosa
How do the kidneys play a role in elimination?
Filters undesirable products such as:
Uric acid
Creatinine
Hormone metabolites
P2 metabolites
In what ways can kidney elimination be supported?
Stop drugs that damage the kidneys e.g. NSAIDs, paracetamol
Avoid table salt
Avoid high animal protein intake
Increase water intake
Address GI dysbiosis
Which herbs can be used to support kidney elimination?
Celery seed
Dandelion root
Nettle
How can beetroot juice support kidney elimination?
Vasodilation
Improved microcirculation
How can blueberries support kidney elimination?
Protects kidneys from gut-derived endotoxins
How can skin elimination be supported?
Avoid toxins on the skins
Saunas - vasodilation/increased perspiration
Epsom salt baths - to open pores and draw out wastes
Burdock root - reconditions the skin
How can lymphatic elimination be supported?
Exercise/movement
Dry skin brushing
Massage
Abdominal breathing