Tox- Nephrotox 1

wilsbach's version from 2016-02-27 16:18


Question Answer
Severe impairment of the circulation has direct effects on renal perfusion. Exs of things which cause severe impairment of circulation, and what can you do to help counter this?(1) Reduced cardiac output often causes renal vasoconstriction-- use ACE inhibitors to battle this. (2) Shock can dec renal perfusion- provide volume. Saline to restart renal excretion
what part of the nephron is most affected by TOXIC tubular necrosis? Why?Accumulation in the proximal tubule, often because reabsorption of toxic molecules takes place there.
why might toxic tubular necrosis happen in the kidney but the liver might not be affected?Renal specific bioactivation (β-lyase, methallothionein) (aka kidney has its own special metabolism paths which might cause toxic activation)
why is kidney one of the organs where we see high toxicity in them?(1) high drug delivery- 20-25% of cardiac output goes to everything in your systemic circulation will end up there in high conc. (2) It has a high metabolic rate and high workload of the cells (so derangement rapidly leads to probs in those cells). High metabolic rate means there is a substantial capacity of bioactivation of compounds in the kidney (3) many transporters in kidney cells playing roles in ACTIVE UPTAKE in the cell-- and diff transporters on basolateral and apical surface of cells means we often see accumulations of toxins in the cell. (4) inc local drug conc in medullary cells/interstitium (5) biotransformation in kidney leading, sometimes, to production of toxic metabolites and reactive intermediates
What are the Specific transporter families of the kidney? (3 types)(deal with uptake of toxin into cells) (1) OATs and OCTs - organic anion and cation transporters (2) OATPs - organic anion transporting polypeptides (3) PEPT - peptide transporters (amino acids and peptides)
what is "MATE"?multi-drug and toxin extrusion proteins-- a family of ABC transporters
what is the name of the biotransformation path the kidney has-- and what phases of biotransformation does it perform?phase 2b and 3: mercapturic acid pathway
The Mercapturic acid pathway: explain what it does Conjugation of GSH (glutathion) to xenobiotics (catalysed by GST). The formed GSH conjugated compounds are removed by ABC transporters. then ɣGT, dipeptidases/ aminopeptidases, N-acetyltransferases metabolize the compound into a stable product.
in the Mercapturic acid pathway/Glutathione conjugate processing, what is the key enzyme? how does it work? what are the variations of this? N-acetyl-transferase (NAT1 and NAT2)<--there are 2 of them.. the more efficacious this enzyme is, the more INACTIVE (not toxic) metabolites are formed. There are genetic polymorphisms in humans and dogs! meaning there are differences in the enzymes of some individuals, so if not as efficacious it will lead to the production of more toxic metabolites.
Mercapturic acid pathway/Glutathione conjugate processing bioactivates what stuff? what is the variation in the metabolism with this path?Bioactivation of certain halogenated benzenes and other toxins (benzene ring structure) (everything with benzine ring does bioinformation though this path ).. there are slow and fast metabolizers (which depends on diff breeds, such as sulfonamide sensitivity in dogs aka dobermans-- they have prob with breaking down benzine type compounds)
Glutathione conjugate processing-- explain the split pathway and the products((he said substances mentioned are not important, what is important is that you know the N-acetyltransferase is important, and that cystine B-lyase is the tox path
in Glutathione conjugate processing/Mercapturic acid pathway, what is the enzyme that causes the non-toxic product and which causes the toxic?NONTOX metabolized by N-acetyltransferase. TOX metabolized by Beta-lyase
Proximal tubular cell transport-- You have the basolateral membrane (in contact with the blood) and the apical membrane in contact with urine. What are the main transportes on the BL memb and which on the apical?BASOLAT: 2 Organic Anion Transporters (OATs). APICAL: Organic anion transporter(OAT), and also a urate transporter (URAT1) and a sodium-anion cotransporter.
explain how probenecid relates to the prox tubular cell transport system (what positive and negative effects can it have?)probenacide is transported but the OAT (organic anion transporter). It uses these transporters to go from the blood, into the cell, into the urine. Probenecid itself doesn't do anything, but bc it has such a high affinity for this xporter, it will go into competition with all other compounds that are also elim through this transporter (such as penicillin) and is an excellent way to extend the pharmacological effects of penicillin bc limits its excretion. So it results in the delay of certain compounds, which leads to inc time of action, OR can be an inc in toxicity. 2 ways this tox can occur: either because of prolonged state of drug in the blood (bc we are delaying its elim) OR because there are 2 OAT xporters on the basolat membrane and only one on the apical memb, probenecid gets into cell and then competes for OAT on apical membrane, and bc there is only one transporter out of that cell, we see an ACCUMULATION OF COMPOUNDS inside that prox tubular cell. and this inc concentration in the cell leads to toxicity--> destruction of cell/cell organelles, and potentially cell death. (cell death is through lipid peroxidation, resulting in ROS)
So we discussed how there are two OAT xporters on blood (basolat) side of renal prox tubular cell, and only one on apical (urine) side, meaning there is risk for accumulation of substances inside the cell. An example of a renal toxin that uses the OAT transporters is OTA (ochratoxin A) how can we use this tricky physiology to our advantage to help with toxic effects?There are co-substrates which compete for the OATs-- which means they protect that prox. tubular cell (remember OTA causes ROSs to form which causes mutagenic effects) bc if toxin is not transported into the cell, then there is no accumulation in the cell, but where does OTA go then? goes back into blood and other kinds of tissues where it could also lead to tox...
2 examples of co-substrates for OATs which can protect prox renal tubule cells from toxin accumulation inside of them?probenacid, and PAH: para-amino-hippuric acid.
so we went over the basic transporters in the prox tubule, but there is a little more to it than that. explain. (what are the xporters doing on the basolat. memb? apical?) on basolat all aiding in excretion, then build up of compound in the cell, and then it depends on how quickly/efficiently it is eliminated into the urine via transporters on the apical membrane. So on the BL membrane there is ONLY excretion, but on apical, there are transporters which do both excretion and reabsorption. MRP 2 and 4/MATE1 and 2 are ABC transporters (they try to protect the boy by transporting things OUTWARDS)....and the Organic cation transporters move things in OR out of the cell. also note there are differences in the numbers of diff types of transporters between BL and apical membrane also (so there is a diff capacity to move stuff between blood and cell and cell and urine) <--implications for tox in prox tubular cell
what is MRP transporter, what is the implications for the particular substrate in the cell? How about MATE1 and MATE2?these are ABC transporters which protect cells by always trying to transport things OUT. so If the compound is a substrate for an ABC transporter, even if it gets transported into the cell by another receptor, the ABCs will push it out again. MATE1 and 2 are ALSO ABC transporters.
in most cases, if a toxic xenobiotic is metabolized, what is the mech of damage?leads to lipid peroxidation and LP leads to formation of ROS (oxidative stress)
what is going on here?This is talking about how metabolism of xenobiotics often leads to lipid peroxidation which forms ROS's leading to oxidative stress. So then, The SOD (superoxide dismutase) aids in conversion of ROS into initially H2O2 and then Glutathione peroxidase (GSHPx) converts it into water. (this is a detoxifying path). So this occurs in both the liver and the kidney.
what are Metallothioneins (MT)? how are they affected by reactive substances? what do they do?Metallothioneins are special metal-species binding proteins-- sort of an acute-phase protein. The MTs are upregulated as soon as sthing strange occurs in the body. Heavy metals, particularly cadmium, bind to and induce the MTs (mostly in liver but also in kidney)-- then that complex of MT+cadmium is transported to kidney and is cleaved due to a pH shift (which is how some of the compounds are released from their plasma proteins)-- this results in free metal ions in the kidney which can lead to accumulation and stress in kidney cell (Free metal ions - accumulation - oxidative stress - cell injury/renal toxicity) so we don't want free metal ion concentrations. But the MTs are helpful bc they bind excessive amounts of cadmium in the blood, making them inactive, until they are in kidney. So, some is elim and others cause tox in kidney. Throughout the body can also bind other metals to get them where they need to be, and also bind up metals to make them inactive till they are where they need to be.

Round-up pesticide: Glycophosphate toxicity

Question Answer
How safe is glycophosphate? when is it not safe?Generally very safe, UNTIL it comes into contact with heavy metals, then it is not safe.
where is there a large source of heavy metals which glycophosphate might be near?heavy metals in fertilizers, in soil, in hard water. So glycophosphate gets into water, then contact with heavy metals in water. Ppl consume water, absorbed, pH of kidney causes them to be released there-->then causes chronic kidney dz
once someone ingests glycophosphates, what path does it take?readily taken up by GI tract, into circulation, release of heavy metals into kidney which results in damage to the kidney.
how does glycophosphate+heavy metal complex affect metabolism of it?INHIBITS CYP450

Ethylene glycol tox

Question Answer
why is ethylene glycol getting ingested in the first place?tastes sweet!
what are some of the effects of EG in the kidney?Acute acidosis, dec perfusion, oxalate crystals in renal tubules.
how does EG affect pH of kidney?acute aciosis
what crystals are formed in tubules after ingestion of EG?oxalate
what is the LD50 of EG like in dogs/cats?1.5ml in cats (woah, really toxic to cats) and 5.5ml in dogs.
is EG tox or are the metabolites tox?metabolites!
explain how EG becomes metabolized to be toxicEG metabolized by alcohol dehydrogenase (same enzyme which converts drinking alcohol) which converts the EG into glycolaldehyde, and glycolate, and glyoxalate, interacts with Ca and ultimately leads to CaOx crystals
explain the metabolic step we want to block in the EG metabolism path, and how we can block it.want to block the alcohol dehydrogenase to prevent the EG from being converted into those other compounds. for DOGS there is a therapy called 4-MP (fomepizol or 4-methylpyrazone) which inhibits the alcohol dehydrogenase. You can also try a competitive inhibition of alc.dehydro. by just giving the animal ethanol (booze!). The competition leads to dec in conversion of EG and avoiding its toxic products. You need to treat this QUICKLY (within 3-6 hours (cats-dogs)
what is the difference in how we treat dogs vs cats for EG poisoning? what should we be cautious about with our treatment?The dog dose does not work in cats. in cats you need a REALLY high dose. but the antidote (ethanol/4-MP) accumulates so be careful of that. Also ethanol and the fomepizole (4mp) can be toxic also. Equally toxic in cats. Then in cats, the dose has to be DEC after the initial HIGH dose***
why is the EG causing renal failure?the oxalate crystals that are formed cut like little knives through all the tubules causing lots of damage. aka Oxalate nephrosis: anorexia, azotemia, oliguria leading to kidney failure
what are the CSs of EG tox?basically clinical signs of renal failure-- vomiting, ataxia, polyuria, see Cardiopulmonary symptoms: tachypnea, tachycardia, but most importantly is the Oxalate nephrosis: anorexia, azotemia, oliguria leading to kidney failure (sharp crystals damage tubules)
you want to tx EG tox quick-- how quick? What other txs can you provide as support aside from the fomepizole (4MP)3 hrs in cats and 3-6hrs in dogs ... you can also Interrupt exposure: induce vomiting (binds poorly to activated charcoal; bentonite is better)... Correct metabolic acidosis: Na-bicarbonate
which toxin binder do you wanna pick for EG?BENTONITE IS BETTER THAN CHARCOAL
**diff between ethanol an fomepizole as tx? implication with catS? dogs?Ethanol goes into competition with the alcohol dehydrogenase, but fomepizole actually inhibits it. Both lead to neg effects in cats but he would rather block the enzyme that give sthing to go into competition--- therefore, fomepizole>ethanol in cats. And in dogs need a lower dose of fomepizole than in cats, so it is even a better choice for them.