41: Toxins

Toxin

Poisonous substance

Toxicity

Degree that a substance can damage an organism

Toxicosis

Pathologic condition induced by a toxin

Xenobiotic

Chemical compound that is foreign to an organism

LD50

The dose that causes 50% of treated individuals to die

ED50

The dose that is an effective treatment for 50% of the treated population

TD50

The dose that causes clinical signs of toxicity in 50% of the population

Categories of toxins

• Chemical

• Pharmaceuticals

• Biologic

Broad mechanisms of toxicity

• DNA damage

• Cell membrane damage

• Block synthesis of proteins

• Destroy or block enzymes

• Block normal physiologic receptors

Factors that affect host response to toxin

• Route of exposure

• Mechanism of action

• Vascular distribution in exposed tissues

• Tissue affinity

• Dose

• Duration

• Individual genetic factors

Types of toxin durations

• Acute: large dose all at once

• Chronic: slow accumulation up until the tipping point is reached

Direct toxicity

The compound itself is damaging without any modification

Indirect toxicity

Toxic metabolites are produced when the toxin undergoes biotransformation

Molecule that is a primary driver of biotransformation

Cytochrome P450

Where is cytochrome P450 found

Endoplasmic reticulum

Liver damage associated with direct toxicity

Periportal hepatocytes (closes to the blood supply)

Liver damage associated with indirect toxicity

Centrilobular hepatocytes (most cytochrome P450)

Where are toxins excreted

Urine and feces

Samples to collect when doing tox testing

Liver and kidney

Why are toxins biotransformed

Normal process to make things hydrophilic for excretion via bile or kidneys

Phase I of biotransformation

Inactivates a compound via hydrolysis or oxidation, making it hydrophilic

How does phase I of biotransformation contribute to causing indirect toxicity

Can cause bioactivation, making a non-toxic compound toxic

Phase II of biotransformation

Conjugation reaction that adds a molecule to make the metabolite more hydrophilic

Where is biotransformation done

In the liver (mostly)

When does damage from direct and indirect toxicity look the same

If untreated, both spread to cause massive damage

Direction of bile flow through the liver

Centrilobular → periportalar

GIT conditions that promotes toxicity

Cholestasis and intestinal obstruction prevents clearance of toxins through the bile

How does bacterial growth impact toxicity

Bacterial overgrowth can interrupt carrier mechanisms and proteins, preventing toxin clearance

Type of toxicity caused by acetaminophen

Indirect

Why is acetaminophen so toxic to cats

Cats don’t have the primary enzymes to do phase II biotransformation on the toxic metabolite that results from phase I of biotransformation. The secondary enzymatic pathways get saturated quickly, glutathione gets quickly depleted, and the leftover metabolite causes problems.

Toxic metabolite of acetaminophen

NAPQI

Blood work signs of acetaminophen toxicity in cats

Heinz body anemia and methemoglobinemia

Source of L-tryptophan

Lush grass

Signs of L-tryptophan toxicosis

Atypical interstitial pneumonia

Type of toxicity caused by L-tryptophan

Indirect toxicity

Why does L-tryptophan damage the lungs and not the liver

Certain cells in the lung play a role in phase I/II biotransformation

Type of toxicity caused by ethylene glycol

Indirect toxicity

Signs of ethylene glycol toxicity

Calcium oxalate crystals in the renal tubules and nephrotoxicity → necrosis

Type of toxicity caused by pyrrolizidine alkaloids

Indirect toxicity

Triad of lesions associated with pyrrolizidine alkaloid toxicity

• Centrilobular hepatocyte necrosis

• Biliary hyperplasia

• Megalocytosis

Type of toxicity caused by aminoglycoside antibiotics

Direct toxicity

Aminoglycoside antibiotic mechanism of toxicosis

Gets stuck in the plasma membranes of the tubules → tubular necrosis

Cause of copper toxicity in Bedlington terriers

Lack of copper binding gene (COMMD1)

Type of toxicity caused by copper storage

Direct toxicity

Mechanism of copper toxicosis

Liver damage → fibrosis → fatal hepatitis