Digestion (week 5) Flashcards
what is biotransformation and elimination?
three phases:
phase1: enzymes modify chemical shape to make it easier to interact with - “activation”
phase 2: enzymes add another (more friendly) chemical group to the product of phase 1, making it more stable and ready for safe removal - “conjugation”
phase 1 and 2 (activation + conjugation) = biotransformation
phase 3: final step of removing the toxin from the body
an empowering approach to detoxification
popular culture:
-quick fixes
-extreme diets
-overnight transformation
scientific approach:
-body’s inherent detox mechanisms
-balanced diet
-healthy lifestyle
this learning outcome:
-chemical process of biotransformation and elimination
-body systems involved
-minimizing exposure and supporting safe toxin elimination
what is a toxin?
widely accepted definition: biological toxins
-webster: “a poisonous substance that is a specific product of the metabolic activities of a living organism and is usually very unstable, notably toxic when introduced into the tissues, and typically capable of inducing antibody formation”
Expanded definition includes:
-environmental toxins: chemicals, heavy metals, pollutants, etc
-pharmaceutical drugs (dose dependent), food additives (colorants preservatives)
-alcohol
Classified by origin:
-endogenous (from within the body) microbial toxins, excess hormones, waste)
-exogenous (from outside)
-xenobiotics - synthetic exogenous compound affecting biology
what makes a toxin toxic?
oxidative stress: damaging cell membranes, tissues, and organs
genotoxicity: causing direct damage to DNA
epigenetic disruption: changing gene expression
endocrine disruption: either mimicking hormones or interrupting their breakdown
enzyme inhibition/disruption: slowing or altogether disabling the function of an enzyme
dysbiosis: destroying healthy microbes and/or promoting the growth of more pathogenic microbes
displacing functional minerals in muscles, bones, teeth, etc
mitochondria and toxins
exceptionally vulnerable to oxidative stress
primary sources of reactive oxygen species during energy production
mitochondrial DNA (mtDNA)
-differs from nuclear DNA
-lack of protective mechanisms = susceptible
toxin exposure:
-disruption of mitochondrial function
-impaired biogenesis
-reduced ATP production (chronic fatigue, neurodegenerative diseases, metabolic disorders, premature aging, etc)
-can lead to apoptosis, programmed cell death
body systems involved
cardiovascular system: pumps essential nutrients, mobilizations of toxins
lymphatic system: drains tissues of interstitial fluid, which contains waste products, cellular debris, and toxins
digestive system: brings nutrients from the intestines to the liver for filtration, returns bile to the intestines for the elimination
renal system: kidneys filter our blood and produce urine to eliminate toxins
the skin: produces sweat, which excretes toxins (heavy metals, BPA, and others)
respiratory system: excretes carbon dioxide and other toxins like alcohol and VOCs, a waste product of cellular metabolism, every time we breathe
enzymes of biotransformation
organ systems: how these compounds are moved around the body
biotransformation: biochemical modifications, specialized enzymes referred to as enzymes as phase 1 and phase 2 enzymes
phase 3 elimination: feces, urine, sweat, breath
foundations first
common fallacies: focus on detox and forget importance of foundational health
examples:
-biotransformation and elimination are nutrient dependent processes and slowed in the absence of a nutrient dense diet
-bile / intestines is the main route for the final elimination - constipation and dysbiosis can impact how much we can eliminate or reabsorb
Phase 1 detoxification - activation
activation phase:
-predominantly occurs in the liver
-some activity in kidneys, skin, intestines, bloodstream
enzymes catalyze reactions: oxidation, reduction, and hydrolysis
-alter the structure of toxins
-introduce functional groups (hydroxyl, carboxyl, amino)
-like adding attachment points for safety handles (phase 2 cofactors)
phase 1 enzymes:
-not limited to detoixification
-activate/metabolize endogenous compounds like hormones
Phase 1 - water solubility
goal: increase water solubility for elimination
-transform hydrophobic toxins into hydrophilic forms
-lipid based cell membranes = lipid soluble compounds cross more easily
-hydrophilic/water soluble compounds less likely to accumulate in tissues
phase 1 intermediates:
-some toxins are ready for removal after phase 1
-others proceed to phase 2
-phase 2 adds cofactors to intermediates for safe removal
phase 1 enzymes: CYP450s
cytochrom P450 enzymes (CYP450):
-primary phase 1 workhorses
-membrane bound enzymes, primarily in hepatocyte cell membranes
-also found in liver, kidneys, adrenal glands, gastrointestinal tract, skin, placenta
-many different types handle different substrates
-enhance water solubility and elimination
phase 1 enzymes: PON1
PON1 (paraoxonase 1)
-high density lipoprotein (HDL)- associated enzyme, circulates in the bloodstream
-acts on various compounds, including organophosphorous (OP) insecticides, nerve agents, plastics, and fragrances
-metabolizes oxidized lipids
-PON1’s ability to break down oxidized lipids = HDLs cardio-protective nature
intermediates
intermediate = has been acted upon in phase 1, but still needs to go through phase 2
-more reactive or toxic = bioactivation
some compounds will become fully inactivated through phase 1 –> eliminated without having to go through phase 2
in most cases, the goal is to prepare for phase 2 detoxification
phase 2 - conjugation
conjugation: neutralizes toxins and enhances water solubility
enzymatic reactions combine the modified phase 1 metabolites with various molecules called cofactors (glutathione, amino acids, sulfate, a methyl group, or glucuronic acid
transferase enzymes
the term cofactor used in two ways:
-those that are being transferred to the toxin
-those that are helping the transferase enzymes to function
6 main phase 2 pathways / cofactors
glutathione conjugation: aka glutathione S-transferase (GST) reaction
amino acid conjugation: amino acids like glycine, taurine, and glutamine
sulfation: uses sulfate ions, resulting in sulfate esters that are highly water soluble
glucuronidation: glucuronic acid, forming glucuronides
methylation: involves the addition of a methyl group to toxins
acetylation: involves the addition of an acetyl group (often from acetyl Co-A)
many chemicals can be processed through more than one of these pathways
redundancy is extremely protective
summary of phase 2
neutralization of toxins: the formation of larger, more complex, more stable, less reactive, and less toxic
increased water solubility: allows toxins to be easily transported in bodily fluids such as blood and urine
transport: once conjugated, the metabolites are transported to various excretory organs (kidney, intestines, skin)
phase 3: elimination
the final step in the body’s detoxification process
relies on a class of transporter proteins that facilitate the movement of conjugated toxins and waste products out of the liver cells
elimination pathways:
-intestines / bile: feces
-kidneys: urine
-skin: sweat
-lungs: exhalation
balancing the phases
overactive phase 1 without adequate phase 2 support = accumulation of reactive intermediates
insufficient phase 1 activity and too much burden on phase 2 = not enough modified substrates for conjugates
various factors can influence this balance:
-genetics, diet, lifestyle, exposure to toxins, and specific cofactors and nutrients
some toxins induce phase 1 enzyme expression, cofactors.
Ex: cigarette smoke
the body burden and half life of toxins
body burden = the current chemical concentration in the body
biological half life = the time to reduce the concentration by half without further intake
example: pesticides
-water soluble, facilitates excretion
-lipophilic pesticides stored in body fat, not easily eliminated. ex: organochlorine pesticides and bioaccumulation
cumulative storage and body burden:
-long exposure: interval relative to half life = time for elimination
-short exposure: interval relative to half life = persistence
bioaccumulation
half life examples
ethanol (alcohol) = 4-5 hours
mercury = ~2 months
PCBs = 2-30 years
other factors affecting bioaccumulation: exposure level, exposure duration, interactions with other chemicals, genetics, age, gender, kidney and liver function, and nutritional status
Regulations & Chemicals of concern
persistent organic pollutants (POPs) aka forever chemicals: organochlorine pesticides (DDT and others), industrial chemicals such as polychlorinated biphenyls (PCBs), dioxins (PCDD and PCDF), furans, and brominated fire retardants
perfluorinated compounds (PFCs): teflon, waterproofing
plasticizers: bisphenol A (BPA), bisphenol S, phthalates
personal care additives: parabens, triclosan, fragrances
food additives: artificial color, synthetic flavoring, preservatives
agricultural pollutants: pesticides and herbicides, glysophate and chlorpyrifos
heavy metals: mercury, arsenic, aluminum, cadmium, lead
excess halogens: floride, chlorine, bromine
air pollution: particle matter (gases, metals, VOCs, ground level ozone)
genetics play a role
detox enzymes are proteins printed from DNA
SNPs (single nucleotide polymorphisms): small variations can change efficiency and speed
Phase 1 examples:
-CYP2D6 “slow metabolizers” have higher risk for adverse reactions to medications
-some variations increase the production of reactive intermediates
Phase 2 examples:
-glutathione D-transferases (GSTs) enzymes detoxify carcinogens, drugs, pollutants
-slower variants in phase 2 pathways = more susceptible to exposures
Phase 3:
-transporter proteins impact the movement of toxins
Ex: metallothionein genes: metallothioneins bind heavy metals (like mercury, cadmium)
-alcohol dehydrogenase genes: affect alcohol metabolism, influencing tolerance and susceptibility to alcohols toxic effects
-DNA repair genes: impact the ability to repair DNA damage from mutagenic and carcinogenic exposures
study of specific gene variants:
-reinforces bioindividuality
-area for continued education
-nutroceuticals can help compensate for some variations
-supporting foundations and minimizing exposures are the highest priority
nutrient dense diet
toxins (fat soluble) > phase 1
phase 1 required nutrients:
-riboflavin (B2)
-niacin (B3)
-pyridoxine (B6)
-folic acid
-vitamin B12
-glutathione
-branched chain amino acids
-flavonoids
-phospholipids
> intermediary stage (less fat soluble)
antioxidant protective nutrients:
-carotenes (vit A)
-coennzyme Q10
-ascorbic acid (vit C)
-thiols (found in garlic, onions, cruciferous veggies)
-tocopherols (vit E)
-selenium
-copper
-bioflavonoids
-zinc
-silymarin
-manganese
> phase 2 required nutrients:
amino acids:
-n-acetylcysteine
-glycine
-taurine
-glutamine
-cysteine
-methionine
> waste products (water soluble)
eliminated from body via:
-bile
-kidneys
-skin
-feces
-sweat
-urine
phase 2 in detail
phase 2 focuses on:
-nutrients providing cofactor molecules for phase 2 enzymes
-nutrients that increase activity of phase 2 transferase enzymes
glutathione conjugation:
-glutathione (tri-peptide: cysteine, glutamic acid, glycine)
-cysteine limiting in synthesis
-sources of cysteine: pork, beef, chicken, fish, lentils, oatmeal, eggs, yogurt, sunflower seeds, cheese
-glycine sources: gelatin, collagen, meats with connective tissue
amino acid conjugation:
-glycine, glutamine, taurine
sulfation:
-sulfur containing amino acids: cysteine, methionine, taurine
-sulfur rich foods: cruciferous veggies, allium veggies, eggs
glucuronidation:
-organosulfur compounds (sulforaphane) from cruciferous and allium plants
-citrus fruit and soy flavonoids
-apiaceous plants: carrots, dill, parsley, parsnips, celery
-teas and herbs including turmeric, rosemary, rooibos tea, green tea
methylation:
-addition of methyl group to toxins
-choline/betaine, B2, B6, folate, B12, choline, magnesium, potassium, sulfur compounds
-sources: beets (high in betaine), radishes, dark leafy greens, eggs, legumes, liver
acetylation:
-addition of acetyl group to compounds
-acetyl-coA as main donor
-dependent on vitamins B1, B5, vit C
phase 2 nutritional themes
themes in phase 2 pathways:
-amino acids from quality proteins
-allium and cruciferous veggies
-polyphenols from colorful herbs and spices
-citrus bioflavonoids
-B vitamins (found in organ meats)
-various phytochemicals can enhance phase 2 enzymatic activity
nutrient dense diet: mineral competition
toxic metals/minerals:
-mimic the structure of other minerals
-compete for receptors and transporters
-ex: chlorine and fluoride competing for iodine uptake
toxic metals are more readily absorbed/deposited when beneficial minerals status is low
some minerals can protect against heavy metals
ex: selenium protects against mercury toxicity