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54 Cards in this Set
- Front
- Back
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definition of toxicology
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exposure to xenobiotics, strange to life
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what is a xenobiotic
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xeno - foriegn and biotic- living, doesnt always mean harmful just not natural
-enters the body from the enviroment e.g. phytochemical or alcohol , preservities, contaminents |
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define nutrition
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the intake of food to provide nutrients
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describe diet as a vector
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predominal route of xenobiotics
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list 7 ways of how diet can be a vector
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1. microbial 2. nutritional 3. enviromental contaminent 4. compounds involved in food production 5. natural toxins (phytoalexins) 6. toxins produces by food processing 6. radionuclides
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All of the ___________ flows through the __________ via the _________________
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all of the mesenteric blood flows through the liver via the hepatic portal system
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What process does the liver play in limiting xenobiotic exposure?
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-the liver gets a chance to remove and metabolize all compounds absorbed from the GI tract before they reach other body tissues , it also regulates the nutrients that are sent into systemic regulation
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All on the _________ returning to the _____ goes first to the ________ and the ______ in the only cappilary bed in the body that receives full _____________.
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All on the venous blood returning to the heart goes first to the lungs. The lung in the only cappillary bed in the body that receives full cardiac output.
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True or fales the lung is sensitive to toxins ... why?
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True. The lung is sensitive to toxins in the venous blood flow including those that bypass the liver or are activated by the liver and those xenobiotics that are absorbed through the skin.
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T or F water soluble metabolites leaver the livr are innocuous. Why?
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Water soluble metabolites that are formed in the liver must pass directly through the pulmonary circulation before they can be excreted in the kidneys so they need to be fairly innocuous.
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The ______ has the greatest ___________ metabolizing capacity and a great capacity for _______________ when injured.
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the liver has the greatest xenobiotic metabolizing capacity and a great capacity for repairing when injured.
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Name organs in the body with xenobiotic metabolizing capacity.
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1. lung 2. skin 3. GIT 4. Kidney 5> liver
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explain the excretion pathways of both wanter soluble and non watersolubles compounds.
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Non water soluble - bile is rich in lipids and acts as a route of excretion for lipophilic compounds, however enterohepatic circulation may occur.
Water soluble compounds- excreted in the urine. |
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explain 3 ways that our bodies can be exposed to xenobiotics.
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orally, topically, inhalation
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Explain the process of exposure to xenobiotics per os / orally.
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1. mixed with food or nutrients
2. exposure to oral or esophogeal epithelia 3. absobed in to the blood stream, flows to liver , one chance at first pass metabolism -after the liver go to lung and all other body tissues |
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Explain the process of exposure to xenobiotics through direct contact to skin.
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1. enters into the venous blood supply goes to the lung and then even distribution to all other tissues in the body.
2. no first pass in the liver 3. gradual clearnce to liver along with all other tissues. |
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Explain the process of exposure to xenobiotics through inhalation.
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1. subsequently even distribution to all tissues in the body
2. no first pass liver clearence 3. gradual clearence in liver and other tissues that have metobolic capacity. |
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why is the liver so good at handling dietary xenobiotics and nutrients?
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-the sinusoid allows oxygen rich blood from the the hepatic artery and nutrient rich blood from the GI tract to swirl together and mix
-the blood swirls past the beds of the hepatocytes -this is when the first past metabolism occurs before the blood continues on the the heart |
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explain how bile production in the liver is an effective way of xenobiotic metabolism
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-the liver synthesizes bile which flows backwards through bile ducts into the small intestien
-the lipid and detergent rich environment can draw back lipophilic type xenobiotics into the liver -some of these lipohpilic materials will be reabsorbed in the GI and a small percent will be excreted -enterohepatic circulation |
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why is the liver resistant to carcinogens
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-rapid cell division increases the chance of DNA damages and rapid cell division has more potential to lose control
-a healthy liver has low levels of cell division -the DNA is kept safe and very compact -when injured the liver can also regenerate its structure however if this is ongoing it can lead to carcinogenic |
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describe the enzymes in the liver that make it beneficial in xenobiotic metabolism
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-liver has high levels of phase 1 enzymes, these can lead to formation of reactive intermediates
-it also has very high levels of expression of phase II enzymes like UDPGT and GST -it also maintains high levels of the major conjugating agents UDP-glucuronic acids and glutathione (GSH) |
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definition of invitro
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in glass- great control over variables
-low systems complexity -potential lack of applicability -e.g. cell free, cell culture -culture conditions need to be appropriet and human cells are better applicability |
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definition of in vivo
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in life-more complex and varieable
e.g. animal models and human models |
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describe strengths and weakeness of animal models experiments
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-whole animals more relavent to systems
-the experimental conditions might not be similar to disease models in human biology -what the animal enviroment is like (stressful) -might not have the same enzymes or pathways exactly |
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name the different human models
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-surveys
-case:control/retrospective -cohort/prospective -intervention studies -cross sectional study |
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describe attributes of a survey study
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no control over behavior
-only association drawn no causation -use Hills criteria |
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describe attributes of a case control study
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retrospective
-2 study populations at starts -healthy and diseased -analyze the previous exposures |
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describe the attributes of cohort study
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-prospective
-follow one healthy population over time and analyze the occurrence of disease and analyze exposures as they happen -collecting data before disease |
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describe the intervention studies with humans
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-the gold standard
-randomized, double blind and placebo controlled -will prove causality but only with the constraints of the model of design -ethical burden of harm |
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describe the process of PCB and dioxins (lipophilic xenobiotics) routes into the body
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-they are very lipophilic and poorly metabolized
-when taken in orally they will be absorbed through the SI and into the liver -the liver can not metabolize these compounds -however it will put some back into the GI to be excreted by enterohepatic circulation -other wise the PCB and dioins will go into the subcutaneous fat and other fatty areas like the fetal brain by VLDL or LDL transport -liophilic xenobiotics will partition in and out of lipid rich transport particles and storage |
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explain HDL role in lipophilic xenobiotics excretion
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-acts as a transport protien in picking up the xeno biotics molecules in the body and returning them to the liver where they can be re-excreted in the bile
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name and explain the first 5 Hills Criteria
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1. Temporal Relationship- exposure always precedes outcome
2. Strength: strong association as measured by appropriate statistical tests (Relative risk) 3. Dose Response relationship: an increase in the amount of exposure will increase the risk 4. Consistency: association is consistent in different studies 5. Biological Plausibility: the association agrees with the current accepted understanding of pathological process |
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in surveys 1.0 OR or RR represents ____________ in risk in the two groups.
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no risk
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in surveys 0.5 represents a group at ___________ risk
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half
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in surveys 1.7 represents a group with __________ % increase in risk.
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70%
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true or false at a 95% CI a rage of 1.3-4.1 is statistically significant
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true the range does not go over 1
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Hills criteria stats that and RR or OR greater than 2.5 or smaller than .5 is significantly strong true or false
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false its greater than 2 or smaller than .5
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give strengths and weaknesses to the human case control survey
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strengths:
-good for low disease incedence -good for long disease latency -easier ethics approval than intervention Weakness: -recall of exposure gives (bias and error) -slection bias in matching case to control -does not prove causality |
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give strengths and weaknesses to the human cohort study
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Strengths: -good controls
-no recall error or bias Weaknesses: long potential wait for disease -low number of cases if disease is rare -expensive - temporarily does not prove causation necessarily |
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give strengths and weakness to the double blind placebo controlled intervention study
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-strengths: you can prove causality within the contrasts of the experimental design
Weaknesses: -tough for ethics approval -long term and expensive -can cause misinterpretation when applied beyond the experimental design to real human populations |
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define endobiotic
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produced endogenously (from whithin the body)
e.g. specialized / oxidized fatty acids, eccasonoids, cholesterol metabolites |
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name 6 differences between xenobiotics and endobiotics
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-most are lipophilic (lipid loving)
-poor air solubility -hard to excrete in urine -excretion in bile will lead to enterohepatic circulation -will accumulate if not metabolized -not handled by normal energy pathways |
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if a lipophilic xenobiotic entered the body what are the three options it has
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1. accumulation
2. Phase 1 metabolism "functionalization" 3. Phase II metabolism "conjucation" |
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explain accumulation as a method of dealing with a lipophilic xenobiotic
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-for some things like PCB and Dioxins it is the lesser of two evils
-accumulaiton in fatty adipose tissue -can lead to a development of toxicity |
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explain Phase I metabolism as a method of dealing with a lipophilic xenobiotic
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-the xenobiotic will make itself functional by adding or exposing a functional group to provide a site for conjugation
-this will produce a risk intermediate that can go through Phase II metabolism -done at cytochrome P450 -some methods are oxidation, hydroxylation, dealkylation, deamination, reduction, epoxidation, |
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explain Phase II metabolism as a method of dealing with a lipophilic xenobiotic
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-seen commonly with pharalogical substance in body
-xenobiotics will go straing to phaseII metabolism -this means conjugating a a side chain to make the xenobiotic water soluble and there fore excretable in the urine -once the side chain is conjugated the product is much less reactive -some e.g. of sides chains are glutathione, sulfate, UPD, methly, acetly |
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what are the 3 possible outcomes of Phase I metabolism
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1. excretion of the phase I metabolite
2. production of the toxix intermediate casues tissue damage, DNA damage -can lead to cancer 3. usually in goes into the Phase 2 metabolism |
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what is another name for the Cytochrome P450
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-mixed function oxidases
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what tissue cytochrome P450 located
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-liver, lung, skin, kidney, and bladder, GIT
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subcellularly where is the cytochrome P450 located
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-in the smooth endoplasmic reticulum, in envelops membranes that ot on the interaction paths of the cell they fuze with pores to the outside of the cell
-secretion of protiens through pores in the cell |
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name the 3 parts of the Cytochrome P450
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1. heme protien:cytochrome P450 - Fe(iron)
2. dual flavoprotien : NADPH-P450 reductase will accept 1e-from NADPH 3. lipidL phosphatidly choline: polar head and two fatty acid side chains to form membrane side chain, required for membrane enviroment |
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what are the two cofactors of cytochrome P-450
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1. NADPH , it is the source of reducing equivalents (electrons)
2. Oxygen: really a substrate, one to water and one to the xeonobiotic typically |
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name the 6 steps in the mechanism of action of cytochrome P450
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1. xenobiotics bind to ferric (Fe3+) form of cytochrom P450
2. 1st electron reduction creates ferrous (Fe2+) cyt P450 - xenobiotic complex 3. binding of oxygen to the cyt P450 /xenobiotic complex 4. elcetron rearangment from Fe2+ and O2 ----> Fe3+ and Oxygen Radical 5. 2nd electron reduction of xenobiotic complex to ,make a very reactive super oxide 6. Oxygen attacks the xenobiotic and it is relased --> ROH and H2O |
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draw the diagram on lecture one slide 22
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do it
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