Protection by N-acetylcysteine of cyclophosphamide metabolism - related invivo depression of mixed function oxygenase activity and invitro denaturation of cytochrome P-450

Cyclophosphamide (CP) at high or repeated doses results in the depression of mixed function oxygenase activities of the liver. Recent studies have attributed this to the interaction between acrolein, a metabolite of CP, and sulfhydryl groups in cytochrome P-450. The present report demonstrates the protection afforded by N-acetylcysteine against acrolein-induced denaturation of cytochrome P-450 $\text{in}\text{vitro}$ and CP-related depression of mixed function oxygenase $\text{in}\text{vivo}$. Co-administration of CP and innocuous chemicals that provide free sulfhydryl groups should, in the future, be useful in enhancing the therapeutic index of CP by either reducing some of the toxicity and/or by allowing the use of repeated treatment with lower but effective doses of CP.