Tox- Hepatotox 1

drraythe's version from 2016-04-29 15:14

liver tox general

Question Answer
What are some of the many functions of the liver?So as soon as there is a problem with the liver, allll sorts of things go wrong
how is liver metabolism a "two way street"?Paths of drugs is similar to paths of toxins, no real diff about what happens to both of them. Vast majority of drugs metabolized into something not toxic, but some drugs are metabolized into toxic metabolites (same with toxins- most metabolized into non toxic compounds but some are activated in the liver by all the systems in place to degrade things)
ex of congenital vs infectious liver dzcongenital: PSS. Infectious: hepatitis virus, bacterial
ex of metabolic vs toxic liver dzsMetabolic: ketosis, fatty degeneration Toxins: acute vs chronic exposure
Secondary modulation of liver functions include?Hormonal and metabolic status, Diet (food/feed ingredients), fever, drugs and toxins (all affect the livers ability to liver)
explain the 3 types of ways to name zones in the liver(1) classic lobule- anatomic classification- the orange hexagon. (2) portal lobule- centered on portal triad- green triangle (pertains to bile secretion) (3) acinus, elliptical or diamond-shaped; divided into zone I (periportal), zone II (transition zone), and zone III (pericentral) (this classification is based on blood flow and metabolism)
some liver lobule anatomy?
where does blood come from (Start) in the liver, and where does it leave the liver? How do we classify this flow?Blood enters at the portal vein--> portal venules (aka interlobular vein) and follows along the acinus, starting in Zone one on the periphery of the anatomical lobule, and moving in towards the central vein it goes through zone 1, then zone 2.
explain how the O2 concentration differs in diff parts of the liver lobule...explain the implicationsThe blood entering the liver is coming from the gut, so it already has a lower O2 content than "fresher" blood. So it starts at the portal vein (interlobular) and it continues to diffuse O2 to hepatocytes as it passes through the lubule-- this means that zone 1 gets the most O2, then zone 2, and zone 3 gets the least O2 meaning AROUND THE CENTRAL VEIN/ZONE THREE IS MOST LIKELY PLACE TO SUFFER HYPOXIC DAMAGE (also the amt of O2 affects the liver metabolism- ie conjugation reactions and CYP450 rxns)
explain how the liver cells communicate- while blood flows within the lobule. What are the diff cells and what do they do?portal vein-->zone 1-->2-->3--> central vein. as it flows through here it encounters. Kupfer cells recognize pathogens. Stellate cells (HSC) (might play role in antigen presentation, other roles, if activated can signal for fibrosis of liver), hepatocytes do metabolism, fibrocytes (responsible for liver cirrhosis) and all of these cells are talking to each other. for these communications they need to be in contact. if kupfer interacting with hepatocyte and there is a intoxication, kupfer will signal, and dec CP450 enzymes.
what are some fnxs of kupffer cells?a phagocytic cell that forms the lining of the sinusoids of the liver and plays role in immune fxn-- can also detect toxic changes in hepatocyte and signal for a dec in activity of CYP450 enzymes
most biotransformation in the body takes place where?liver, duh.
whats a xenobiotic?a foreign chemical substance found within an organism that is not normally naturally produced by or expected to be present within that organism.
explain the basics of biotransformation again- where does a toxic substance start, what are the phases of biotransformation?Xenobiotic= foreign substance. IF THEY ARE LIPOPHILIC, go into phase I biotransformation (oxidation, reduction, hydrolysis) and becomes more hydrophilic. Then (or if it started out hydrophilic) it can either enter PHASE 2 biotransformation (conjugation) and then be excreted via bile or urine, or is just directly excreted.
which phase of biotransformation is CYP450 part of, what implications might this have?it's part of PHASE I metabolism, and according to this flow chart only lipophilic compounds really go through phase I.
what is pre-systemic elimination and why do i carethe LIVER does this bc blood from gut goes to liver before it reaches systemic circulation- I care because it's really nice toxic things get metabolized before they go to my heart and brain and such.
what is another place you might see bioactivation/inactivation?High level of biotransformation reactions (GIT, nasal mucosa and lung!) and KIDNEY!! (said in class: in GI might lead to pre-systemic clearance-- breaking down compounds in GI tract accounts for fact not absorbed, dont end up in systemic circulation)
two reasons liver has High potential for energy production? (1) High level of intermediary metabolism (the intracellular process by which nutritive material is converted into cellular components—called also intermediate metabolism.) (2) High internal exposure to xenobiotics
Biotransformation pathways: Most biotransformation enzymes are highly expressed in the liver.. what are some of these bioxformation paths doing?(1) Deactivation of physiological transmitters (hormones and neurotransmitters (2) physiological homeostasis (3) Bioactivation of drugs and toxins (4) liver specific injury (bc breaking down things might activate them, and liver is ground 0)
one of the major challenges in veterinary medicine pertaining to the liver is Species differences in Drug Metabolizing Enzymes-- what are some of these differences?(1) Genetic differences (2) Strain and breed differences (3) Genetic polymorphisms (geneticists use the term genetic polymorphisms to describe the inter-individual, functionally silent differences in DNA sequence that make each human genome unique)
what are the 3 major factors that play a role in liver biotranformation/drug metabolizing enzymes?(1) Nutrition (2) Environment (3) diseases
most biotransformation enzymes live in which zone?zone 3. (implications for zone specific damage)
most CONJUGATION enzymes live in which zone?zone 3 also (wiki: Products of conjugation reactions have increased molecular weight and tend to be less active than their substrates, unlike Phase I reactions which often produce active metabolites.)
the location of biotransformation enzymes might then predict liver path. example.Aflatoxin B1 toxicity: centro-lobular necrosis. bc that's where enzymes are so that's where activation takes place, so affects those cells first.
Zone-specific cell damage--> what things/metabolism is happening in Zone 1? (periportal)Most aerobic, contains glutathione, glutathione peroxidase and alcohol dehydrogenase (antioxidant reactions!!)
Zone-specific cell damage--> what things/metabolism is happening in Zone 2? (midzonal)Gradual transition from zone 1 to 3 (closer to 3, the stronger the dec in O2 content. in general not as important as zone 1 and 3)
Zone-specific cell damage--> what things/metabolism is happening in Zone 3? (midzonal)Least aerobic, contains CYP450, CYP450 reductase, lipid synthesis takes place here (BIOTRANSFORMATION/hydroxylation+CONJUGATION)
if a toxin needs to be activated, which zone will you see damage in?ZONE 3 (because that is where biotransformation/CYP450 is)
what are the main situations where there will be ischemic damage to the liver? O2 or nutrient shortages, vasoconstrictive chemicals. (anything with ischemia affects liver strongly. ) (vasoconstrictive chemicals often in plants. vasocontriction--> ischemic damage)
Toxic responses of the liver--> Cytotox--> cocaine, alcohol affect which zone?Zone 1 (alcoholy dehydrogenase in zone 1 (And drink it, absorbed from GI, first part of liver in contact to is zone 1 zone around portal vein. )
Toxic responses of the liver--> Cytotox--> CCl 4 , benzopyrine, PCBs, aflatoxins, pyrrolizidine alkaloids, acetaminophen affect which zone?ZONE 3-- site of biotransformation. (and conjugation)
Toxic responses of the liver--> Cholestasis: what results from this (CSs)?hyperbillirubinaemia
Toxic responses of the liver-->Steatosis--> what is this and what zone is damaged? triglyceride accumulation (zone 3 damage) (bc that is where lipid synthesis takes place!)
Toxic responses of the liver-->Cirrhosis what is this and what part of the liver is responsible for this?dysfunctional scar tissue formation (stellate cells)
Toxic responses of the liver--> Cholestasis: what is this? what are the 4 reasons it can happen?Definition: Inhibition of the excretion of bile salts or phospholipids. Reasons: (1) Inhibition of the excretion via MRP2 (anions, GSH, bilirubin) (2) Injury of the bile duct epithelium (3) Bile duct occlusion (bile stones) (4) Injury of hepatocytes
how does bile get from the hepatocytes to the bile canniculi?MRP2, which is an ABC-transporter (moves bilirubin, anions, GSH (glutathione-disulfide reductase aka antioxidant enzyme) too)
The liver is often the first organ affected after ___ exposure to toxic substancesoral (think portal vein)
what do Hepatocytes do?has broad spectrum of biotransformation enzymes that deactivate (first pass) or activate toxins
what do Kupffer cells do? (macrophages that are easily activated by LPS inducing a local or generalized inflammatory response (see also synthesis of acute phase proteins and cytokines)
what can liver endothelial cells tell us (what are the sensitive to)?sensitive to reactive oxygen/nitrogen species
what do stellate cells do?promoting liver cirrhosis, but may also activate oval cells (liver regeneration)
Impairment of hepatocyte function results in liver-specific as well as a variety of metabolic effects. Examples are: (4)(1) Impairment of protein synthesis (2) Impairment of detoxification pathways (3) Impairment of bile acid processing and transport (4) Hepatocyte injury is accompanied with a switch in fatty acid metabolism (fatty liver degeneration) and loss of vitamine A synthesis
which vitamin needs to liver to be synthesized?Vitamin A (remember cats can't eat too much liver bc OD on vit A!)
liver tox--> Impairment of bile acid processing and transport leads to what sequalea? jaundice/icterus and bile duct hyperplasia; steatosis
liver tox--> Impairment of detoxification pathways leads to what sequalae? urea and hepatic encephalopathy, secondary neurotoxicity, anorexia
liver tox--> Impairment of protein synthesis leads to what sequalae? hypo-albuminemia; delayed clotting time, reduced synthesis of immunoglobulins (secondary immune suppression), as well as growth retardation and production losses (milk, meat and eggs)
Impairment of hepatocyte function (or direct cytotoxicity). Impairs all biotransformation processes, including (3 things)(1) Phase 1 (CYP450 and MFO) (2) Phase 2 conjugation reactions (3) Transport proteins
Impairment of hepatocyte function (or direct cytotoxicity). Impairs all biotransformation processes, including phase 1... explain the sequelae of thisPhase 1 (CYP450 and MFO) mediated processing of hormones, neurotransmitters (COMT) is delayed or incomplete. Drug metabolism (therapy) is impaired (dose adjustment - minus 25% of the standard dose)
if you have impaired phase I metabolism but need to provide drug therapy, how should you dose them?25% less than the standard dose (less metabolism= work stronger and longer)
if you have impaired Phase 2 conjugation reactions due to liver tox, what can happen?UDP-GT, GST, ST and others build up
if you have impaired transport proteins because of liver tox, what happens?inhibition of Organic anion/cation transporters, ABC transporters, resulting in an intracellular accumulation of toxic metabolites and cytotoxicity (Glutathione S-transferases (GSTs) )

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