Toxicology

Xylitol

• Artificial sweetener found in sugar-free chewing gums, candies, baked goods, and some medications

• Xylitol is a potent stimulator of insulin release in dogs, unlike in humans

• Causes rapid and profound insulin release → leads to severe hypoglycemia

• Clinical Signs

  • Hypoglycemia: weakness, ataxia, lethargy

  • Neurological: seizures, collapse, coma

  • May progress to hepatic necrosis in severe or delayed cases (from secondary hepatic injury)

• Diagnosis: Based on history of exposure (sugar-free gum, etc.), clinical signs, and laboratory findings (low blood glucose)

Nicotine

• Tobacco plants, cigarettes, chewing tobacco, nicotine gum, or insecticides (nicotine sulfate)

• Neonicotinoids are related insecticides (e.g., imidacloprid, nitenpyram).

• Nicotinic receptor agonist at autonomic ganglia and neuromuscular junctions

• Low doses: stimulate receptors

• High doses: cause depolarizing blockade → paralysis

• Affects CNS, cardiovascular, skeletal muscle, and GI systems

• Clinical Signs

  • Acute Toxicity

    • Neurologic/muscular disturbances: tremors, ataxia, seizures

    • Cardiovascular: tachycardia, hypertension (sympathetic stimulation)

    • Respiratory failure due to diaphragmatic paralysis → death

    • GI signs: salivation, vomiting, diarrhea

  • Chronic Toxicity 

    • Ocular, dermatologic, and respiratory diseases due to tobacco smoke

• Initial stimulation of ganglia and neuromuscular junctions → excessive firing

• Followed by blockade → flaccid paralysis

• Death from hypoxia due to respiratory muscle paralysis or cardiac arrest

• Reproductive/Developmental Toxicity

  • Nicotine and related alkaloids can cross the placenta → cause teratogenic effects

  • Mechanism involves increased intracellular Ca²⁺ and ROS, leading to embryonic apoptosis and malformations

  • Swine most sensitive species

  • Arthrogryposis, flexure/lateral rotation of carpal joints, spinal deformities (lordosis, scoliosis), cleft palate

Common Herbicides

• Paraquat (bipyridyl herbicide)

• Glyphosate (Roundup®)

• Phenoxyacetic acids (2,4-D; MCPA)

Mechanisms of Action

Clinical Signs

• Paraquat: vomiting, diarrhea, respiratory distress, pulmonary fibrosis, renal failure

• Glyphosate: hypersalivation, vomiting, diarrhea, anorexia

• 2,4-D: vomiting, myotonia, ataxia, seizures, renal tubular necrosis

Pathophysiology

• Paraquat accumulates in lungs → redox cycling → ROS → type I & II pneumocyte necrosis

• 2,4-D causes neuromuscular overexcitability and oxidative injury

• Glyphosate mostly causes GI mucosal irritation

Blister Beetle Toxicity (Cantharidin Poisoning)

Source

• Epicauta spp. beetles in alfalfa hay — dogs exposed if they eat contaminated hay (or lick contaminated feed).

Toxic Principle

• Cantharidin — potent vesicant (blister-forming agent).

Mechanism of Action

• Causes disruption of desmosomal junctions in epithelial cells → blistering and ulceration of GI and urinary tract mucosa.

• Also absorbed systemically → renal tubular and myocardial necrosis.

Clinical Signs

• Hypersalivation, vomiting, hematemesis, diarrhea (may contain blood), dysuria, hematuria, colic, depression, shock.

• Possible sudden death from hypovolemic or cardiogenic shock.

Pathophysiology

• Cantharidin irritates mucous membranes → erosions and ulcers in esophagus, stomach, and intestines.

• Causes cystitis and hematuria by damaging urinary epithelium.

• Myocardial necrosis may lead to arrhythmias.

• Death often due to electrolyte imbalance, shock, or myocardial failure.

Plant Toxicity in Dogs

Common Toxic Plants

Food Toxicity in Dogs

Key Toxic Foods

Cleaning Product Toxicity

Types and Mechanisms

Pesticide Toxicity

Common Groups

Hepatic Biotransformation Phases

Phase I: Functionalization (Modification)

• Purpose: Introduce or expose a polar functional group (–OH, –NH₂, –COOH, etc.) via oxidation, reduction, or hydrolysis.

• Main enzymes:

  • Cytochrome P450 monooxygenases (CYPs) — e.g., CYP1A, CYP2E1, CYP3A, CYP2D subfamilies.

  • Flavin-containing monooxygenases (FMOs)

  • Esterases, amidases, alcohol/aldehyde dehydrogenases

Mechanism (example: oxidation by CYP450):

1. Substrate (RH) binds to CYP’s hydrophobic pocket (in smooth ER membrane).

2. NADPH donates electrons through cytochrome P450 reductase.

3. O₂ is split; one O atom is inserted into substrate (→ ROH), the other reduced to H₂O.

4. Product is more polar—or occasionally reactive (toxic intermediates).

Dog-specific notes:

• Dogs have unique CYP isoform expression patterns, e.g. limited CYP2C activity relative to humans.

• Certain dog breeds (e.g. Greyhounds) have lower CYP1A2 activity—affecting metabolism of some anesthetics and toxins.

Phase II: Conjugation (Synthetic)

• Purpose: Couple the Phase I product (or parent compound) to an endogenous substrate to increase solubility for biliary or urinary excretion.

• Main conjugation pathways:

  • Glucuronidation – via UDP-glucuronosyltransferases (UGTs)

  • Sulfation – via sulfotransferases (SULTs)

  • Glutathione conjugation – via glutathione-S-transferases (GSTs)

  • Acetylation and methylation

Canine considerations:

• Dogs have relatively poor acetylation capacity (low N-acetyltransferase activity), affecting detoxification of aromatic amines and hydrazines.

• They do perform glucuronidation efficiently, unlike cats (which are deficient in UGT1A6/UGT1A9).

• Sulfation and GSH conjugation are generally robust in dogs.

2. Mechanisms of Hepatotoxicity

Hepatotoxicity occurs when:

• Reactive metabolites bind covalently to proteins, lipids, or DNA.

• There’s oxidative stress from reactive oxygen species (ROS).

• Mitochondrial dysfunction or membrane disruption occurs.

• Bile flow is impaired (cholestasis).

• Apoptosis/necrosis pathways are triggered.

Molecular cascade example (paracetamol/acetaminophen toxicity):

1. Normally, acetaminophen → glucuronide/sulfate conjugates (safe).

2. Small fraction oxidized by CYP2E1/CYP3A to NAPQI (N-acetyl-p-benzoquinone imine), a highly reactive electrophile.

3. NAPQI detoxified by conjugation with glutathione (GSH).

4. In overdose (or depleted GSH), NAPQI binds hepatocellular proteins → oxidative stress, mitochondrial permeability transition → necrosis.

5. Dogs are somewhat more resistant than cats, but massive doses still overwhelm GSH.

3. Cellular Physiology: How Hepatocytes Handle Xenobiotics

Cellular effects of hepatotoxins:

• Membrane lipid peroxidation → loss of integrity.

• Cytoskeletal collapse → “ballooning” degeneration.

• ER stress → unfolded protein response.

• Mitochondrial depolarization → ATP depletion.

• Kupffer cell activation → inflammatory cytokines (TNF-α, IL-1β).

4. Examples of Canine Hepatotoxins and Mechanisms

5. Protective & Adaptive Responses

• Induction of detox enzymes (CYPs, GSTs, UGTs)

• Upregulation of antioxidant defenses (SOD, catalase, GSH peroxidase)

• Autophagy & mitophagy – remove damaged organelles

• Cell proliferation – regenerative nodules if injury sublethal

Failure of these compensations → acute hepatic failure (centrilobular necrosis pattern typical of toxic injury).

6. Key Takeaways (Canine-Specific)

• Dogs: competent glucuronidators but poor acetylators.

• CYP polymorphisms and breed variability affect susceptibility.

• Hepatotoxins damage through reactive intermediates, oxidative stress, and disrupted cell signaling.

• The liver’s ability to regenerate can mask early subclinical damage.

• Biomarkers: ALT ↑ (hepatocellular leakage), ALP ↑ (cholestasis), bilirubin ↑.