19. liver toxicants

what are 5 factors that predispose the liver to toxicity?

1. first pass effect

2. enterohepatic circulation

3. unique functions like bile formation/excretion

4. major site of metabolism (bioactivation)

5. zones of liver affected differently due to blood & oxygen supply

mechanism of acetaminophen toxicity

• metabolized to NAPQI → hepatotoxicity

  • forms protein adducts

  • ROS — lipid, DNA, protein oxidation

  • necrosis

• oxidizes hemoglobin in dogs & cats

  • p-aminophenol (PAP) metabolite → methemoglobinemia

    • chocolate-colored blood, heinz body anemia

major organs/systems affected by acetaminophen toxicity

blood (methemoglobin), liver

acetaminophen treatments

• liver protectants, antioxidants, SAM, N-acetylcysteine (bind metabolites + GSH precursor)

• cimetidine in dogs only — inhibit CYPs to block formation of NAPQI

  • cats are poor glucuronidators; ↓↓ alternate metabolism

• methylene blue — carefully consider adverse effects

mechanism of methylene blue treatment

reduces methemoglobin to hemoglobin

source of blue-green algae toxicity

• cyanobacteria that can produce toxins — neurotoxins & hepatotoxins

  • microcystin = hepatotoxin

• occurs in warm weather

• nutrient enriched waters

• stagnant waters

mechanism of blue-green algae toxicity

microcystin inhibits phosphatase types 1 and 2A in hepatocytes, leading to:

• cytoskeletal damage

  • apoptosis, cell death

• mitochondrial damage → ↓ energy production

• generation of ROS → oxidative stress

• tumor promotion; cancer

major organs/systems affected by blue-green algae toxicity

GI, liver, or CNS based on type of toxin

what major mushroom species can cause hepatotoxicity?

• amanita phalloides “deathcap”

• amanita virosa “destroying angel”

mechanism of mushroom toxicity (a. phalloides)

• amatoxins (α & β amanitin derivatives)

  • most potent; absorbed best

  • bind RNA polymerase II → block protein synthesis

    • high-protein synthesis cells are most sensitive

• phallotoxins & virotoxins irreversibly polymerize hepatic actin filaments, triggering hepatic cholestasis

major organs/systems affected by mushroom toxicity

GI, liver

mechanism of iron toxicity

• direct caustic or irritant effects on GI mucosa

• once iron-carrying capacity of serum has been exceeded, free iron is deposited in the liver & other tissues

  • direct mitochondrial poison

  • ROS

  • lipid peroxidation

• also causes hemolysis via ROS and reduces heme synthesis

major organ/systems affected by iron toxicity

GI, liver

iron toxicity treatments

• decontamination

  • GI protectants

  • activated charcoal does NOT bind iron well

• supportive treatment

  • milk of magnesia — complex with iron

  • chelation therapy if iron levels are >300 mcg/dL

    • deferoxamine — iron chelator

may take days to recover & should be monitored for 4-6 weeks

what genetic defect leads to copper storage disease in dogs?

• deletion mutation that eliminates a major section of COMMD1 (copper metabolism gene)

• heterozygous dogs do not accumulate Cu or develop clinical signs

• dogs with 2 abnormal genes can accumulate Cu, leading to clinical signs

mechanism of copper toxicity

• pre-hemolytic phase: excess copper stored in lysosomes

• hemolytic phase: ↑↑ copper → lysosome ruptures

• release of copper causes cell damage & rapid release into bloodstream

  • redox cycling, oxidative stress, & lipid peroxidation → mitochondrial + cellular damage

  • release of hepatic copper to RBCs & kidneys leads to severe hemolysis + renal necrosis, also via generation of ROS

• pre-hemolytic → hemolytic phase often stress-induced

major organs/systems affected by copper toxicity

GI, blood, liver

in which species does copper toxicity not cause a hemolytic crisis?

camelid species, such as llamas/alpacas, although extensive liver necrosis remains a consistent manifestation

copper toxicokinetics + large animal species/breed sensitivities

• more likely to be toxic if low dietary intake of molybdenum & sulfur — complex with copper in tissues to help excrete in urine + feces

• sheep are more sensitive than cattle & goats

  • breed differences in susceptibility in sheep

• jersey cattle are more susceptible than other breeds