4.9.6 Organ Toxicity Models
Organ-specific toxicity models are used both to study the mechanisms of drug-induced organ injury and, extensively, to screen candidate hepatoprotective,...
Organ-specific toxicity models are used both to study the mechanisms of drug-induced organ injury and, extensively, to screen candidate hepatoprotective, nephroprotective, and other organ-protective agents, particularly in phytochemical and natural-product research.
Hepatotoxicity — Carbon Tetrachloride (CCl4)-Induced Model
Drug- and chemical-induced liver injury is modelled using carbon tetrachloride, a classical hepatotoxin that is metabolised by hepatic cytochrome P450 2E1 to the highly reactive trichloromethyl free radical, which initiates lipid peroxidation of hepatocyte membranes and consequent centrilobular hepatocellular necrosis. CCl4 (commonly administered as a 1:1 mixture with olive oil, at approximately 1–2 mL/kg intraperitoneally, either as a single dose for acute injury or repeated doses for a fibrotic/chronic injury model) produces a reproducible and mechanistically well-characterised pattern of liver damage in rats. Hepatoprotective efficacy is assessed through serum liver enzymes (ALT, AST, ALP), histopathological grading of centrilobular necrosis and inflammatory infiltrate, and, in chronic protocols, collagen deposition indicative of fibrosis. Silymarin is the standard reference hepatoprotective comparator. A paracetamol (acetaminophen)-overdose model, exploiting the analogous formation of the reactive metabolite NAPQI via CYP2E1, provides a clinically relevant alternative hepatotoxicity model directly paralleling the most common cause of acute liver failure in human overdose.
Nephrotoxicity — Cisplatin- and Gentamicin-Induced Models
Drug-induced kidney injury is modelled using two clinically important nephrotoxic agents acting through distinct mechanisms. Cisplatin (a single dose of approximately 6–8 mg/kg intraperitoneally in rats) produces proximal tubular injury through direct DNA cross-linking, oxidative stress, and mitochondrial dysfunction in tubular epithelial cells, closely modelling the dose-limiting nephrotoxicity that constrains cisplatin's clinical use as a chemotherapeutic agent. Gentamicin (typically 80–100 mg/kg/day subcutaneously for seven to ten days) produces a distinct pattern of proximal tubular injury through lysosomal phospholipidosis following aminoglycoside accumulation in tubular cells, modelling the nephrotoxicity associated with clinical aminoglycoside antibiotic use. Both models are assessed through serum creatinine and blood urea nitrogen (indicating reduced glomerular filtration), urinary biomarkers of tubular injury (including N-acetyl-beta-D-glucosaminidase and, increasingly, the sensitive biomarker kidney injury molecule-1, KIM-1), and histopathological grading of tubular necrosis. These models are extensively used both to elucidate nephrotoxicity mechanisms and to screen candidate nephroprotective agents intended for co-administration with the nephrotoxic parent drug in clinical chemotherapy or antibiotic regimens.