Physiology of Xenobiotic Metabolism and Scientific Studies Flashcards
What are the three interactions between toxicology and nutrition?
- Food as a source of xenobiotic exposure
- Effect of nutritional status on xenobiotic metabolism
- effect of xenobiotic exposure on nutritional status
describe a nutritional xenobiotic
overconsumption of macronutrients and micronutrients, food additives
describe a microbiological xenobiotic
salmonella, botulinum
describe an environmental xenobiotic
persistent organic pollutants, mercury, dioxins
describe food contamination xenobiotic
synthetic pesticides
describe food processing xenobiotic
polyaromatic hydrocarbons, nitrosamines
describe a plant xenobiotic
phytochemical, natural pesticides
describe an example of an effect of nutritional status on xenobiotic metabolism
sulfer amino acid deficiency and acetaminophen metabolism
describe an example of an effect of xenobiotic exposure on nutritional status
alcohol consumption and vitamin A deficiency
Explain excess protein intake in relation to renal dysfunction
- excess protein intake a day is anything over 100g a day
- metabolic acidosis which results in increased urinary excretion of nitrogen and calcium
- decreased urinary pH and decreased reabsorption of calcium in the kidney
- increases bone resprption to maintain blood calcium levels and as a result increases the risk of bone fractures
explain excess intake of total calories and obesity
- habitual over-nutrition in the form of calories over time can result in obesity
- increased risk of co-morbidies (t2d, CVD, cancer)
What is botulism
a serious illness caused by the botulinum toxin
- the toxin causes paralysis that starts in the face and can spread to limbs
describe food borne botulism
harmful bacteria thrive and produce the toxin in environments with little oxygen (ie home-canned food)
describe wound botulism
if these bacteria get into a cut, they can cause a dangerous infection that produces the toxin
describe infant botulism
this is the most common form of botulism
- begins after the bacterial spores grown in baby intestinal tract
describe DDT
- insecticide used to reduce malaria risk
why is DDT less effective
many species of mosquitoes ave developed resistance
why is DDT harmful
- accumulates up the food chain,
- fat soluble
- toxic to humans
describe the human toxicity of DDT
- liver damage including liver cancer
- nervous system damage
- congenital disabilities
- reproductive dusfunction
What are PCBs
polychlorinated biphenyls
- organic chlorine compounds
Are PCBs resistant? How so?
they are extremely perisistent
- last for many years because they do not break down on their own and they are hard to destroy
where do PCBs originate?
- ingredients in many industrial materials
- used to make coolants and lubricants for electrical equipment
What is TCDD?
Dioxin
POP
herbicide
agent orange
How does TCDD/Dioxin work?
- binds to the aryl hydrocarbon receptor and functions as a transcription factor
properties of dioxin
- carcinogenic
- teratogen
- low water solubility
- fat soluble
- half life of 7-8 years
what causes chloracne
dioxin/tcdd
What does PAH stand for
poly aromatic hydrocarbons
what are PAHs
- class of carbon and hydrogen containing molecules
- non polar
- lipophilic
- result from incomplete combustion of organic materials
- also produced on charred foods
- carcinogen
what is the food processing xenobiotic that is created by charring food, typically meats
PAH
how are PAHs created
incomplete combustion of organic materials (coal, cigs)
what is an example of a PAH
benzo-a-pyrene
what was the consequence of PAH exposure within the industrial revolution
scrotal cancer
what is HCA
heterocyclic amines
how are HCAs formed
formed when amino acids, sugars and crating or creatinine react at high temperatures during the cooking of meats
describe the structure of HCS
5 or 6 carbon ring with nitrogen
what is an example of an HCA
PhIP
What is nitrosamines
a food processing xenobiotic
how are nitrosamines produced
produced from nitrites (used to cure meats) and secondary amines)
if a food source likely has nitrosamines, what will it also contain
sodium nitrite
without metabolism and excretion, where do lipophilic xenobiotics go in the body
they will accumulate in lipid rich regions or tissues of the body (brain, adipose tissue)
what risk increases when lipophilic xenobiotics accumulate in the body
risk of toxicities and adverse effecrs
- neurotoxicity
- cancer
how do you get rid of lipophilic xenobiotics so they dont accumulate
have to metabolize the xenobiotic to convert them from a lipophilic parent compound to a water soluble metabolite that can be excreted in the urine
where does nutrient rich blood from the GIT mix with oxygenated blood
in the liver in the sinusoids
everything leaving the liver goes where?
hepatic vein
where do large lipophilic xenobiotics go from the liver
they go to the lymph in a chylomicron along with large dietary lipids
describe blood flow from liver sinusoids to heart
- sinusoids
- central vein
- hepatic vein
- inferior vena cava
- heart
where does phase 1 and 2 reactions happen
in the hepatocytes
describe hepatocyte contact with sinusoid and bile canaliculi
- each hepatocyte is in contact with both the sinusoid and the bile canaliculi
- this permits the movement of xenobiotic or xenobiotic metabolites across the hepatocyte cell membrane (they can move between the sinusoids, hepatocyte and bile canaliculi)
what organ produces bile
liver hepatocytes produce bile which contains bile acids
what is the purpose of bile acids
bile acids aid in lipid digestion by acting as a detergent or emulsifier
what is the polarity of bile
bile is amphipathic (water and lipid soluble)
how do lipophilic xenobiotics bind with bile acids
bile has the ability to bind or trap lipophilic xenobiotics and transport them to the small intestine in the enterohepatic circulation
- lipophilic xenobiotics bind with bile acids in the hepatocyte and enter into the bile canaliculus which connects to the bile duct
how are lipophilic X Brough to the liver via the HPV
lipophilic xenobiotics can be bound to bile salts/ acids in the intestine which brings them in to the liver Bia the HPV
what happens to xenobiotics when the reach the liver depends on two things:
- liver expression of the phase 1 enzyme (CYPs): will impact how much phase 1 reaction is possible and how many reactive intermediates are produced
- liver expression of phase 2 enzymes and conjugating agents: determine how much phase 2 reaction is possible
describe the ideal speed for phase 1/2 reactions
- ideally phase 1 reactions happen slowly and controlled so that phase 2 reactions can keep pace with phase 1 reactions for reduced risk of DNA damage
- ideally phase 2 reactions will happen fast
Once lipophilic xenobiotics reach the liver, what happens if liver hepatocytes do nothing?
xenobiotic will leave the liver and phase1.2 reactions can happen outside the liver in another tissue
once lipophilic xenobiotics reach the liver, what happens if phase 1 reaction only happens
the reactive intermediate (xenobiotic metabolite) will leave the liver and either:
- damage DNA in another tissue
- phase 2 reaction will occur in another tissue and the product will be excreted
once lipophilic xenobiotics reach the liver, what happens if both phase 1 and 2 reactions happen
the water soluble xenobiotic metabolites leave the liver to the kidney and then are excreted in the urine
once lipophilic xenobiotics reach the liver, what happens if the xenobiotic is bound to bile acids
the lipophilic xenobiotic will be trapped in the enterohepatic circulation
where does the blood from GIT go
all of the blood from the GIT goes directly to the liver via the HPV
what organ gets first chance to metabolize and remove compounds absorbed by GIT
the liver gets 1st chance
what are extra hepatic tissues
tissues that are not the liver
generally, what does the liver regulate
the liver regulates how much xenobiotic or its metabolites reach the other tissues of the body, and how harmful they are
what has implications on how effective pharmaceutical drugs are
first pass metabolism by the liver
all of the venous blood returning to the heart goes where
all of the venous blood returning to the heart then goes to the lung
what organ is most vulnerable to xenobiotocs/metabolites that are in venous blood flow
the lung
what organ has greatest xenobiotic metabolizing capacity
the liver has the greatest xenobiotic metabolizing capacity and a great capacity to regenerate when injured
when does the liver synthesize bile
- immediately after first pass metabolism
- after xenobiotics or xenobiotic metabolites are delivered to the liver via venous blood flow
what are the three natural routes of xenobiotic exposure
skin
lung
oral
describe action of topical xenobiotic exposure
direct action/exposure on skin
describe action of inhalation xenobiotic exposure
direct action/exposure on lung
describe the action of per of xenobiotic exposire
direct action/exposure on GIT
describe where xenobiotic goes after topical exposure
- encountered on skin
- x passes into localized capillary bed in skin
- x travels into Venus blood
- lung is first major capillary bed that x goes to
- x is then distributed to all tissues of the body
is there first pass metabolism in topical exposure
no
describe where xenobiotic goes after inhalation exposure
- encountered in lung
- x is evenly distributed to all tissues
is there first pass metabolism in lung exposure
no
describe where xenobiotic goes after per os exposure
- oral, esophageal, and GIT encounter x
- x must cross both apical and basolateral membrane of the epithelial cell to enter blood or lymph
- x goes to liver for first pass metabolism
what are the 2 possible fates of large lipophilic x in small intestine
- bind to bile/bile acids so that it enters HPC
- then goes to liver and is trapped in ECH - incorporated into a chylomicron and circulate in lymph first
- then through systemic circulation and return to liver in a chylomicron remnant
once in the liver what are the two fates of x/x metabolite
- trapped in EHC
2. X leaves liver via hepatic vein, goes to inferior vena cava, then heart, lung, then body
what xenobiotics will accumulate in lipid-rich tissues?
PCB, dioxins, mercury
- resist metabolism and have very long half lives
when a xenobiotic acumulates in subcutaneous adipose tissue what happens
dioxin causes choracne
what happens when xenobiotic accumulates in fetal brain
neurotoxicity, death
what happens when xenobiotic accumulates in adult brain
neurotoxicity and cognitive dysfunction
what are sinusoids
3D structures that allows the oxygen rich and nutrient-/x-rich blood mixes and flows past hepatocoyes for first pass metabolism
what stores and releases biel
gall bladder
why is liver resistant to carcinogenesis
low levels of cell division
- when liver is injured it can regenerate its structure via cell division
describe topical and inhalation models
- commonly used to mimic those types of natural human exposures
- well-controlled dose and timing of x
- no first pass metabolism
describe IV/IM injection model
- IV: x enters venous circulation, reaches the lung, then distributes throughout the body
- IM: x enters muscle, then venous circulation, then lung
- well controlled dose and timing of x
- no first pass metabolism
- not physiologically similar to natural human exposure
describe oral xenobiotic model
- x is mixed with food
- x may unintentionally react with food ingredients
- dose and timing of x is dependent upon animals food intake
- vulnerable to first pass metabolism
define ad libitum
eat as much or as often as desired
describe gavage injection
ball-ended needle is inserted down esophagus and injects x into stomach
describe gavage model
- well controlled dose and timing
- no food interactions
no composure to oral/esophageal tissues - vulnerable to first pass
benefits of in vitro study model
- great control over variables
- low system complexity
- follows scientific method, proves casualty
- often short and least expensive
- minimal ethical burden
negatives of in vitro study
- low system complexity
- potential lack of human applicability
- ethical burden
benefits of in vivo study
- control over many variables
- varying system complexity
- follows scientific method
negatives of in vivo study
- less control over variables
- potential lack of human applicability
- ethical burden
what are knockout mice
a genetically modified mouse in which researchers have inactivated or knocked out an existing gene
what is an inducible knockout mouse
chemical inducing agent exposure will knockout gene of interest
- researchers control when gene is no longer expressed
what are reporter mice
a gene encoding a fluorescent, bioluminescent proteins or biochemical tag are inserted into the genome
- when gene is expressed and translated into a protein, that protein will be fluorescent and can be detected
describe human intervention invivo study
- randomized, double bladed, placebo-controlled human intervention or RCT is described as the gold standard
benefits of human intervention study
- control over some variables
- high system complexity
negatives of human intervention study
- high system complexity
- potential lack of human applicability
- lack of human applicability
- ethical burden
- long duration and expensive, or short and misleading and still expensive
benefits of surveys- observational studies
- applicable to human health
- limited ethical burden
negatives of surveys- observational studies
- limited control over variables beyond study design
- no control of behaviour
- no randomization
- no intervention
- does not prove causality, only association
what is a case-control/retrospective survey
- 2 populations at the start; diseased and healthy
- effective for low incidence and long latency diseases
- effective for capturing life-long behaviours
benefit of case-control/ retrospective survey
shorter and less expensive than cohort
negative of case-control/retrospective survey
- real of exposure information introduces error and bias
- control group may not be optimally matched to case group
- case and control groups may not be representative of general population
what is a cohort/prospective survey
- one population at the start, all healthy
- effective for high incidence and short latency diseased
benefit of cohort/prospective survey
- less real error/ bias
- control group optimally matched to diseased group
negative of cohort/prospective survey
- selection of starting population may be biased
- larger sample size needed, more expensive
may not accumulate disease outcomes of interest
what is an odds ratio and relative risk/risk ratio
estimates of the strength of association between an exposure and an outcome
what is the interpretation of a OR or RR of 1
no statistical significant difference in the risk of the outcome between the exposed and unexposed groups
what is the interpretation of a OR or RR of 0.5
one group is at half risk of the outcome as the other group
what is the interpretation of OR or RR of 0.7
one group has a 30% decreased risk of the outcome
what is the interpretation of OR or RR fo 1.7
one group has a 70% increased risk of the outcome, or 1.7-fold risk
if the confidence interval contains 1:
there is no statistically significant difference in the risk of the outcome between the exposed and unexposed groups
p- value of <0.05
less than 5% chance of false positive result, meaning researchers are 95% confident in the stated outcome
