Suppression of plasma glutathione peroxidase activity by ifosfamide

Plasma glutathione peroxidase (GPx) is synthesized predominantly in the kidneys. Plasma-GPx activities were measured in 12 patients with gynecological malignancies before and after chemotherapy. The patients were treated with cisplatin alone (P); with VP16 and cisplatin (EP); with cyclophosphamide, doxorubicin, and cisplatin (CAP); or with ifosfamide, doxorubicin, and cisplatin (IAP). The protein levels of the enzyme were semi-quantitatively determined by immuno-blot analysis. Plasma GPx activity was decreased by an average of 61% (p < 0.01) in patients treated with IAP, while no significant decreases were observed in patients treated with any drug combinations without ifosfamide. Immuno-blot analysis of plasma samples from a patient treated with IAP revealed no differences in the protein levels of plasma GPx either before or after IAP administration, although the plasma GPx activity decreased 83%, from 0.173 to 0.029 units/ml. The results indicate that the decrease in plasma GPx activity was not due to impaired production of the enzyme in the kidneys, and that ifosfamide is responsible for inhibition of the enzyme activity. Since GPx is an enzyme of major importance in detoxification of lipid peroxides in the brain, CNS toxicity induced by ifosfamide might be related to severe suppression of plasma GPx activity.