Inter-individual variation in cisplatin-induced liver injury is associated with hepatic platinum accumulation and GSH/GST-dependent defense in male mice

Cisplatin is a platinum-based chemotherapeutic agent whose clinical use is limited by toxicity in non-tumor tissues. Even among genetically homogeneous mice receiving the same dose, hepatic responses to cisplatin vary considerably, but the biochemical basis of this variability remains unclear. Male mice received a single intraperitoneal dose of cisplatin, and hepatic injury was evaluated using serum alanine aminotransferase (ALT) activity. Cisplatin significantly increased serum ALT activity, with marked inter-individual variability among treated mice. Within the cisplatin-treated group, higher serum ALT activity was associated with higher hepatic platinum retention and oxidative protein damage, whereas lower serum ALT activity was associated with higher glutathione S -transferase (GST) activities toward multiple substrates, increased GSTP1/2 expression, higher reduced glutathione (GSH) content and GSH/GSSG ratio, and greater glutamate-cysteine ligase (GCL) activity and GCLC expression. Notably, several parameters, including reduced GSH content and GCL activity, showed no significant differences between the control and cisplatin-treated groups, highlighting biochemical patterns that were apparent primarily at the individual level. These findings suggest that inter-individual differences in hepatic platinum handling and GSH/GST-dependent defense capacity are associated with variability in cisplatin-induced hepatotoxicity and emphasize the biological significance of within-group variability in experimental toxicology.