Increased glutathione levels and activity of PON1 (phenyl acetate esterase) in the liver of rats after a single dose of cyclophosphamide: a defense mechanism?

The clinical utility of cyclophosphamide (CYP) as an anticancer drug is limited by its urotoxicity and nephrotoxicity and to a lesser extent by its hepatotoxicity. The present study was undertaken in order to find out the reason why liver is least susceptible of the three organs to CYP-induced damage although it is the major site for drug activation and metabolism. Adult female Wistar rats weighing 200-250 g were administered single intraperitoneal injection of CYP at the dose of 150 mg/kg body weight and sacrificed at various time intervals 6, 16 or 24h after the dose of CYP. The control rats were administered saline alone. Hepatotoxicity was assessed by measuring plasma alanine aminotransferase (ALT) activity and histopathology of the liver. Liver was used for the assay of reduced glutathione; activity of paraoxonase (PON1) malondialdehyde - marker of lipid peroxidation. Serum was used for the assay of ALT activity and PON1 activity. The level of reduced glutathione in the liver CYP treated rat was increased by 22% and 57% at 16 and 24h, respectively. Interestingly, a marked increase in the activity of PON1 (122%) was observed in the livers of CYP treated rats 24h after treatment. This was accompanied by significant increase in PON1 activity (23%) in the serum. No significant alteration in hepatic malondialdehyde level was observed at any time period after treatment. Serum ALT activity was increased slightly 24h after treatment with CYP. Mild liver damage was observed histologically only 24h after treatment with the drug. The present investigation shows for the first time that an increase in antioxidant levels in the liver may be a defense mechanism to prevent/minimize CYP-induced liver damage.