Aminoglycoside nephrotoxicity is characterized by proximal tubular cell injury. The sub-mechanism by which gentamicin causes oxidative damage to tubular cells involves which intracellular pathway?

• A Gentamicin accumulates in lysosomes of proximal tubule cells, inhibiting lysosomal phospholipases (phospholipidosis) and generating reactive oxygen species through iron-gentamicin complex formation ✓
• B Direct mitochondrial electron transport chain inhibition reducing ATP production
• C Inhibition of megalin-cubilin receptor complex preventing normal tubular protein absorption
• D Activation of renal tubular NF-kB pathway producing IL-1beta-mediated tubular apoptosis

Explanation

Gentamicin enters proximal tubule cells via the megalin-cubilin endocytosis receptor and accumulates in lysosomes. It inhibits lysosomal sphingomyelinase and phospholipases, causing phospholipidosis. Critically, gentamicin forms complexes with iron (iron chelation from ferritin), and this gentamicin-iron complex catalyzes the Fenton reaction, generating hydroxyl radical (OH•) and other reactive oxygen species — leading to oxidative injury to mitochondrial membranes, disrupting energy production and triggering tubular cell apoptosis. Megalin-cubilin inhibition would actually be protective (preventing drug uptake), not causative. NF-kB activation plays a role but is downstream of the primary oxidative mechanism.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.