Tox- Hepatotox 3

kelseyfmeyer's version from 2016-10-02 23:28


Question Answer
Cats are not small dogs--> what is the mutation cats have, and what does this imply for their liver metabolism?Felidae have a mutation in exon 1 of UGT1A and a low expression of UTG2B (this is Glucuronosyltransferase) AKA THEY DO NOT GLUCORONIDATE WELL. Then, their Alternative pathways have a very limited capacity: sulphation is one option but this often leads to toxic metabolites.
list off the bunch of drugs which are MAINLY glucuronidated, meaning cats are going to have a whopper of a time trying to metabolize them (leading to higher rates of toxicity)Acetaminophen - phenytoin (anti-epileptic) - hexobarbitone (barbiturate sedative) - propofol - carbonates - chloramfenicol - sulphonamides - phenols and ketones (plant-derived)
big pic of the whole acetaminophen biotransformation pathways
what kinda metabolism is glucuronidation vs hydroxylation? (what enzyme, what phase metabolism, which zone of liver)GLUCORONIDATE: Glucuronosyl transferase (UDP) enzyme, this is CONJUGATION so it occurs in zone 3. HYDROXYLATE: CYP450, this is BIOTRANSFORMATION and it occurs in zone 3
how do dogs vs cats differ in their metabolism of acetaminophen?DOGS (and ppl) can glucuronidated nicely and doing so results in non-toxic compounds. CATS don't glucoronidate well, so they generally hydroxylate via CYP450 instead, which results in the production of the very toxic compound NAPQI
what are the clinical signs/results of acetaminophen tox in cats (what substance is causing the issue?)because they dont glucoronidate, they hydroxylate the aceto. into NAPQI and these toxic effects are seen: Methaemoglobinemia (cyanosis, dyspnea, polypnea)--> **Felidae: low activity of methaemoglobin reductase, so then also get Methaemoglobinuria (brown discoloration of urine). Also get Facial edema, hypothermia, vomiting, anorexia, and Liver failure (later then in dogs)
how much acetaminophen is toxic to a cat?(10) - 50 mg/kg is toxic (said in class: avg weight of cat- say its 10kg. so if you give cat one pill you'd give yourself, you're about to kill that cat. half falls within toxic range. DON'T GIVE YOUR CAT TYLENOL )
what are the clinical signs/ results of Acetaminophen tox in dogs?Methaemoglobinaemia (4-12h following ingestion). Cyanosis, tachypnea, dyspnea, depression, discolored urine (although dogs can glucoronidate, they also N-acetylate which results in toxic effects-- proly if too high a dose, the glucoronidate path gets overwhelmed). Liver injury (para-aminophenol induced; 36h following ingestion). Abdominal pain upon palpation, vomiting, jaundice, elevated liver enzymes (ALT and ALP).... and Non-specific: slight leg edema
(said in class) owner runs in with dog that ate a bunch of tylenol-- what do?make sure they vomit, then activated charcoal or something that binds, aggressive fluid therapy-- all comes down to minimizing exposure, esp minimizing exposure to liver. after absorption in circulation-- if can get rid of through diuresis- do it (so fluids).
Dogs vs cats with acetaminophen.. Dogs have a higher biotransformation dependent tolerance... why?diff between dog and cat-- dog ultimately has a diff diet. cats in general are strictly carnivores and dogs are more omnivores. so widest metabolism abilities (and subst of CYP450) is in herbivores bc eat plants and plants have more chemicals than meat, so herbivores have the best CPY450 system. but cats are strict least amount of metabolic ability. ogs somewhere in the middle-- which is why dos have a higher biotransformation tolerance.
Threshold doses resulting in clinical side effects (orientation)-- for dogs? cats?Dogs: 50-200 mg/kg BW, Cats: (10) 20-50 mg/kg BW (and Human adults take 1000mg q8h)
why are cats at a disadvantage with aceto. and what is the main CS? metabolism mediated sensitivity already at low doses (dont glucoronidate so immediately to toxic pathways)- present predominantly with methemoglobinemia
how do dogs with aceto. tox present? present with clear clinical signs of liver failure (at high, repetitive doses-- when glucoronidate path overwhelmed, then takes more toxic paths)
(how do humans present with aceto. tox?)liver function impairment. Saturation of glucuronidation and sulfate conjugation. CYP induced formation of NAPQI. Impairment of bile acid secretion - yellow stool

Intervention stratagies

Question Answer
what are the 4 (general) measures to reduce liver injury?(1) Reduce exposure (2) Reduce absorption (3) Improve elimination (4) Modulate biotransformation
rule in red box about dx vs txTreat (intervention) the patient first and then complete your diagnostic work-up! Then in green box: There is no specific antidote for most liver toxins: treat the patient first and then complete your diagnostic work-up
Prevention of absorption: 3 options? (1) Carbo medicinalis: activated charcoal (2) Silica clays (sepiolite) (3) mineral clays: bentonite
explain how activated charcoal works. how much do you give and how do you give it?Absorbing surface 1gram= 500-1500 m 2! It binds water (so might be able to tx diarrhea), Binds most chemicals (with the exception of solvents including alcohol). Use as a suspension: 1-3 mg/kg bw (fill the stomach)
explain how mineral clays work. What are they commonly used in?Bind polar toxins like aflatoxins! and alkaloids! Widely used as feed additives in farm animal practice (Mineral clays: montmorillonite is the main constituent of the volcanic ash weathered product known as bentonite (related substances are spoilt, smelted and many others in different geographical regions) )
The anti-oxidant dream... why are antioxidants helpful? what do they do?Oxidative stress leads to non-specific mechanisms of cell injury. Anti-oxidants can reduce this oxidative stress. Radical scavengers and inducers of SOD, CAT, GSH and GPx. There are many plant anti-oxidants, like Silymarin - Ginseng - Brassica spp. - citrus, etc.
2 methods to protect liver cell fxn is.. (categories)(1) combating oxidative stress (2) modulating biotransformation
how can toxins induce oxidative stress in liver cells?through formation of oxygen free radicals (ROS=reactive oxygen species) which are non-specfic mechanisms of tox.
you can treat free radicals by inactivating them with scavangers... what are the antioxidant enzymes? (4)SOD, CAT, GSH(glutathione-disulfide reductase), GSHPx
where (zone) does free radical scavenging (GSH induction) happen in?Zone 1
where does biotransformation occur? how can you modulate biotransformation to help preserve liver cell function (which phase metabolism should you make do what)Biotransformation phase 1 and phase 2 occurring in zone 3... want to INHIBIT PHASE I (this is CYP405 aka hydroxylation which often makes the toxic compounds) and want to INDUCE phase 2 (conjugation- often inactivates dangerous things)
Radical scavengers: what is their main effect? on a cellular level? on a molecular level?
which vitamins work like scavangers?vit c plays role in minimizing oxidative stress. Vit e important in getting rid of the oxygen freeras
chart that shows how radical scavengers help preserve the liver and its function
sooo what is UDP again?This is the glucuronidation enzyme (Uridine 5'-diphospho-glucuronosyltransferase)
sooo what is GSH again?glutathione-disulfide reductase enzyme-- responsible for conjugation and/or free radical scavenging
what is SOD, CAT, GSH, GSHPx? explain how they work together.Antioxidant enzymes! SOD (Superoxide dismutase is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide (O2−) radical into either ordinary molecular oxygen (O2) or hydrogen peroxide (H2O2))... CAT is catalase, GSH is glutathione, and GSHPx is glutathione peroxidase which is in mitochondria. basically the SOD's turn free radicals into OH and H2O2, and then catalase and GSHPx convert the H2O2 into H20 and 02 (now harmless instead of causing nonspecific cellular damage)
what''s the problem with trying to fix liver function?there is usually no specific antidote bc there is usually no specific problem it's causing, just call death etc
why do free radicals happen?cell membrane is destroyed (lipid perodixation) and they are released
what are free radicals? what is an antioxidant?unpaired electron which can destroy cell membranes... has a free electron it can donate to the free radical.
CSs of free radicals?generally non-specific damage
explain the breakdown pathway of a free radical by an antiocidanthave free radical. Then have SOD (supraoxie dysmutatase) which can convert it into hydrogen peroxide. Then catalase turns it to water and glutathione peroxidase into regulat O2. These 3 enzymes are key in the breakdown of oxygen free radicals. The problem is, it takes a few days before they actually have an effect. And you need to give them several times a day to allow them to work sufficiently. (so not good for treating acute phases)
which process often forms ROSs?lipid peroxidation
what is vitamin E important in? Vitamin C?Vitamin A takes up one of those free radicals, important in getting rid of the O2free radicals. but to get rid of them needs vitamin C-- so they work together.
glutathione plays important roles in...preserving liver fxn, preserving the liver in general, and the prevention of oxygen free radicals.
sulfhydrobonds and sulfide groups also important when talking about preserving the liver and its fxn-- why? give an example of one of these.aid in free radical processing, aid in chemoprotection. N-acetyl-cysteine (NAC) is such a substance-- it is quite easy to cleave off its sulfide group (SH group) and this SH group can then be donated to enhance glutathione (GSH) synthesis
what is N-acetyl-cysteine (NAC) what does it do?can donate it's sulfide group (SH) which can then be used by GSH to improve it's radical scavenging function. (can also remember that it is a mucolytic bc it cleaves the SH bridges in mucus so good for bronchopneumonia. ALSO binds NAPQI so helps in tylenol intoxications... it is also renal protective bc it has an effect on the beta-lyase pathway ((kidney specific metabolism pathway) it also chelates metals so has an effect on heavy metal intoxications.
what is s-adenosyl-methionine (SAMe)? what does it do?It INDUCES GSH (glutathione) synthesis. So methionine is converted into s-adenosyl-methionine (SAMe)...this leads to SAH and homocysteine,which are both toxic. But, homocysteine has a really important role bc it can be converted into glutathione (GSH). so through admin of adenosylmethionine (SAM) we can start induction of the production of glutathione. but depends a bit on how quickly homocysteine is converted into GSH via transsulfuration pathway. If it takes too long, can be converted into toxic substances, or SAH (Beware of toxic metabolites: s-adenosylhomocysterine) can linger and be toxic too. SO, SAMe can be used as an antioxidant bc induces production of glutathionine (GSH).
vitamins in general help protect liver cells how? via cell membrane stabilization
benefits of preventing lipid peroxidation (And which things do this?)(vitamins do this)
explain how vitamins (And which vitamins) help stabilize cell membranes. What are the 4 major players?They prevent lipid peroxidation! (lipid peroxidation is what causes the free radicals to be formed in the first place). Vitamin A, E, C, and selenium all play a role in this. selenium through enhancing GSH (glutathione) and GSHPx (glutathione peroxidase). So vitamin E can convert free radicals into non-reactions species (E= α-tocopherol (direct membrane stabilizing) ) Then vitamin A takes up that electron, becomes reactive itself, but it is when recovered by vitamin C on the membrane surface. so immediate production of these free radicals as a result of lipid peroxidation are sort of stopped right at the beginning if you use vitamin E and C. And vit E is lipophilic so likes to sit in cell membrane and have an effect there. OFten times this requires the co-admin of selenium, bc Se enhances GSHpx
modulation of biotransformation--> what are the two options for this?(1) inhibition of CYP450 (2) induction of glutathione (GSH)/ UDP (glucuronidation) <--both of these are. So basically inhibit phase 1 metabolism and induce phase 2 metabolism.
*what is oltipraz, what does it do?prevents formation of epoxides by inhibition of CYP1A2 and CYP3A4 (alfatoxin B1),and it also induces phase 2 enzymes (GSH, UDP) it inhibits bioactivation of compounds and it aids in elim of compounds through inactivation via phase 2. [in class said need to know this oltipraz, that it inhibits CYP450, it is extremely expensive)
enhance excretion--> need to know where the substance is eliminated! If excreted in bile, what can we do, and how?can inc biliary excretion. So there is a bile acid, Ursodeoxycholic acid (UDCA). You can use it in all processes with cholestasis bc it enhances biliary secretion and also protects against toxins by protecting cells in your bile ducts (cholangiocytes). Also stim hepatobiliary secretion and also protects hepatocytes.
what is UDCA and what does it do?Ursodeoxycholic acid, inc biliary secretion as a way to protect liver cells (more on other card)
antioxidantstake a while to start to be effective