Session 7 - Liver Detoxification Flashcards
What are the functions of the liver?
- bile production
- filtration & storage of blood
- 500 vital functions
- stores iron & vitamin a
- processes toxins like acetaldehyde in alcohol metabolism
- metabolism & detoxification
- regeneration
What are the role of kupffer cells?
Serve as a first line defense against immunoreactive material passing from GIT via portal circulation.
They are the resident macrophages in liver and account for 80-90 of total number of natural macrophages. They release cytokines, chemokines etc
Can regenerate.
What is the purpose of bile?
- carrier of toxic substances
- removes products of detoxification from liver
- emulsifies dietary fats for digestion
What does the detoxification and biotransformation of exogenous substances involves?
- hepatic filtering and phagocytosis
- intestinal microbiota and gut-associated lymphoid tissue (GALT)
- phase 1 liver detoxification pathway
- phase 2 liver detoxification pathway
What are the purpose of the two detoxification pathways (3rd role)
to render endogenous and xenobiotic substances more water soluble and easier to excrete. Allows neutralization of unwanted chemical compounds (pesticides, drugs, medicines)
What happens in phase 1 pathway?
Small chemical changes making compounds more hydrophilic for elimination by kidneys or further acted upon by phase 2.
What is the important enzyme in pathway 1?
Heme Dependent enzymes (phase 1 reactions):
Cytochrome p450 (cyt) makes toxic compounds (fatty acids, steroids, xenobiotics) water soluble so they can be excreted.
What is a cofactor for Cytochrome P450?
Iron & NADH
What neutralises free radicals produced by phase 1 liver metabolism of chemical toxins?
Glutathione
What is glutathione (reduced from GSH) made up from and what is its function?
Amino acids: glutamine, glycine, and cysteine.
Acts as an antioxidant in phase 1
Conjugates heavy metals in phase 2
What nutrient replenishes glutathione?
Vitamin C
What are the cofactors for enzyme glutathione reductase?
Riboflavin/B2,
niacin/B3
vitamin c
What are the cofactors for Phase 1 detoxification?
Vitamin C, copper, magnesium, zinc, thiamin, riboflavin, niacin, b6, folate, b12, iron, branch chain amino acids.
What can an underactive Liver 1 pathway manifest an intolerance to?
Intolerance to perfume, caffeine, sugar cravings, bloating, constipation, abnormal fat metabolism. Environmental chemicals. An overactive Phase 1 can result in excess free radical production.
What are inducers of phase 1?
Drugs, environmental pollutants, pesticides, high protein diets, saturated fats, indoles from cruciferous vegetables
What are inhibitors?
phytochemicals in foods: grapefruit juice, curcumin from turmeric.
What foods assist in functioning of Liver Detox Phase 1?
Cuciferous vegetables, green tea, selenium, methionine.
What does Liver detoxification Phase 2 involve?
The conjugation (change) of intermediate metabolites made in phase 1 with glucuronide, sulphate, or glutathione.
The biotransformed water soluble toxicants are excreted via the bile and faeces or kidneys & urine.
What are the required nutrients for phase 2?
Amino acids, vitamins, minerals.
What are the inducers and inhibitors of phase 2?
Inducers: cigarette smoking, birth control pills, Phenobarbital, limonene-containing foods
Inhibitors: Low protein diet, Non-steroidal anti-inflammatory drugs (e.g. aspirin), tartrazine (yellow food dye), Aspirin, probenecid (gout medication).
What are the 3 main enzyme systems which metabolises alcohol?
- Alcohol and acetaldehyde dehydrogenases
- Microsomal ethanol oxidising system (MEOS) using cytochrome P450 enzymes.
Catalase
What cofactor is required for these enzyme systems?
Iron
What nutrients are alcoholics deficient in?
Iron, zinc, vitamin a, b vitamins.
What are the effects of alcohol on liver enzymes?
ALT - released when liver is damaged
ALP- an enzyme elevated during liver injury.
GGT - marker of liver injury (most sensitive biomarker of alcohol consumption)
What nutrients can support alcohol detoxification?
Vitamin B3 (metabolise alcohol)
Glutamine (precursor to GABA - decreases cravings and relieves alcohol detoxification)
Phenylalanine
List other nutrients to support alcohol detoxification.
Cruciferous vegetables Glutathione Vitamin B Complex Selenium Iron (cofactor for C450) Zinc (cofactors for DNA damage repair enzyme) Nuts Vitamin A Proteins Carnitive Antioxidants A, C
What are the signs and symptoms of phase 1 liver pathway induction?
Bloating, tiredness, sweating at night, itchy skin, headaches, allergies, poor sleep, gut problems. Toxic metabolites travel in the blood rather than being excreted.
What will be the nutritional impact of dysfunctional phase 1 in the body?
- overburdening of phase 2
- activation of kupffer cells leading to excess release of cytokines
- depletion of nutrients (gutathione, niacin)
What could be one of the biochemical reasoning pathways for bloating?
Toxic TMAO travel to gut (gut-liver axis) and harms microbiome and gut epithelium causing bloating.
Which over the counter meds are detoxified via phase 1?
Salicylates and ibuprofen
What are the largest macrophages with phagocytotic activity for the protection of liver cells called?
Kupffer cells
Which group of enzymes are imperative for liver detox 1?
Cytochrome 450 (group of haem dependent enzyme)
True or false? Curcumin and grapefruit cause an upregulation of phase 1 liver detoxification.
False they cause a lowering of phase 1
True or false - Glutathione is required as a cofactor for detoxification pathway to support cytochromes.
False – it is required as an antioxidant in phase 1 and as a conjugant in phase 2.
What is the form of glutathione that acts as an antioxidant?
Reduced Glutathione GSH
GSH is depleted by the oxidative by-products of phase 1, the GSH-dependent phase 2 activity is inhibited.
T/F - Vitamin C is required as a cofactor for glutathione peroxidase enzyme
False
Selenium is required as cofactor for glutathione peroxidase enzyme (it’s a selenoprotein)
Which primary nutrients ensure the optimal functioning of phase 1 liver detoxification?
Vitamin C Magnesium Zinc Copper Which all help with optimal functioning
Which nutrients are required as cofactors for excretion of thyroxine, catecholamines and oestrogen via sulphation pathways?
Sulphation pathways require pyridoxine, methionine, cysteine, glutathione, taurine and molybdenum as cofactors.
Which of the following induce the phase 2 liver detoxification pathway?
Cigarette smoke, birth control pills and limonene
NSAIDS, low protein diet and tartrazine inhibit this pathway
T/F - Acetyldehyde dehydrogenase, MEOS and catalase are the enzymes involved in alcohol metabolism
True - The enzymes alcohol dehydrogenase (ADH), cytochrome (CYP2E1), and catalase all contribute to oxidative metabolism of alcohol. ADH, (in cytosol), converts alcohol (i.e., ethanol) to acetaldehyde (using NAD+). Catalase, (in peroxisomes), uses H2O2 to oxidize alcohol. At excessive levels of alcohol, CYP2E1, in the cell’s microsomes (MEOS), becomes active. Acetaldehyde is metabolized finally by aldehyde dehydrogenase (in mitochondria) to form acetate.
