Lecture 12: toxicity of liver and GI tract 1

what is the order of the hepatic zones farthest in to farthest out

periportal zone

midzonal

centrilobular zone

hepatic zone 1

most oxygenated, less susceptible to hypoxia, first to encounter toxins from GIT

hepatic zone 3

least oxygenated, more susceptible to hypoxia, area where most metabolic transformation occurs

factors that affect hepatic toxicity uptake and concentration

first pass effect

close contact with circulation/ large amount cardiac output

accumulates metals and vitamins

iron homeostasis

copper homeostasis

enterohepatic recycling

where is bioactivation and metabolism for hepatic toxicity commonly seen

zone 3

necrotic liver injury can be

focal, zonal, bridging, or massive and panlobular

where does zonal necrosis of the liver commonly occur

zone 3

bridging necrosis describes

confluent zones of necrosis that extend between zones of the lobule and between lobules

panlobular or massive necrosis denotes

hepatocyte loss throughout the lobule with loss of lobular architectures

where are pyrrolizidine alkaloids commonly found

Boraginaceae, Compositae and Leguminosae.

what do pyrrolizidine alkaloids cause

irreversible hepatic damage; toxicity signs are consequence of impaired liver function

what animals are highly resistant to pyrrolizidine alkaloid toxicity

Small herbivores such as sheep, goats, rabbits, guinea pigs and other herbivorous laboratory animals

due to low rate of hepatic production of reactive metabolites and a high rate of activity of detoxifying enzymes

toxic principles of showy rattlebox

monocrotaline and spectabiline

what type of damage does showy rattlebox cause

hepatic and pulmonary damage

toxicokinetics of tansy ragwort

contain high levels of alkaloids

what affects might happen to cattle if they eat high amounts of tansy ragwort

liver necrosis

pyrrolizidine alkaloids mechanism of toxicity

potent electrophiles so they react with nucleophilic substrates including DNA, proteins and AA

primary organ of intoxication for pyrrolizidine alkaloids

liver

clinical signs of pyrrolizidine alkaloid

acute intoxication show signs of acute liver failure,

including anorexia, depression, icterus and edema.

Chronically intoxicated animals may present with photosensitivity, icterus and

increased susceptibility to other liver insults.

pyrrolizidine alkaloid diagnosis

high elevation of liver enzymes: increase bilirubin and bile salts are seen

most common form of mycotoxins

mushrooms

should you identify a mushroom based on a picture?

NEVER consult a mycologist

most dangerous mushroom

death cap or destroying angel

amanita phalloides

toxic principle of mushroom toxicity

amatoxins and phallotoxins

mechanisms of toxicity for mushrooms

inhibiting nuclear RNA polymerase

decrease in messenger RNA results in decreased protein synthesis and cell death. Cells with high metabolic rate such as hepatocytes, renal tubular cells and GI epithelium are most vulnerable

toxicokinetics of mushrooms

amanitins are well absorbed from the GI tract and have short half life

clinical signs of mushroom toxicity

what mushroom type is known to cause hallucinogens

psilocybe spp. - psilocybin

what is the single most dangerous plant to dogs

sago palm ( cycads)

toxic principles of sago palm

cycasin causes hepatic necrosis and GI effect

beta-methylamino L-alanine is a neurotoxic AA causing muscle weakness, paralysis and seizures

mechanism of toxicity of sago palm

mutagenic, carcinogenic, and teratogenic

what animal is extremely susceptible to aflatoxicosis

turkeys

what will you see microscopically with aflatoxins

liver is enlarged and shows marekd fatty accumulations and massive centrilobular necrosis and hemorrhage

what product is notoriously susceptible to aflatoxin contamination

peanuts

what animals are susceptible to cocklebur toxicity

pigs, ruminants and horses

signs of cocklebur toxicity

weakness, vomiting, twisting neck, weak pulse

characteristic histologic lesion of cocklebur

severe, diffuse, centrilobular hepatocellular necrosis

trifolium spp toxicity is primarily in

horses

trifolium spp toxicity leads to

chronic liver failure

copper toxicity sequence

what animals are most susceptible to copper toxicity

SHEEP, also cattle, goats and dogs