Role of glutathione in the metabolism-dependent toxicity and chemotherapy of cyclophosphamide.

The role of glutathione in the biological effects of cyclophosphamide (CP) was evaluated by investigating the following: effect of CP on hepatic glutathione levels; relationship between hepatic glutathione depletion (repletion) and the binding of [chloroethyl-3H]CP and [4-14C]CP to hepatic macromolecules; effects of interaction between CP (or acrolein) and diethyl maleate (a classical glutathione depletor), and/or between CP and cysteine on the binding of labeled CP to hepatic macromolecules, on the induction of hematuria, on the content of hepatic cytochrome P-450, on weight gain in rats, on survival in mice, and on the chemotherapeutic efficacy of CP against Walker 256 carcinoma in rats. CP and acrolein produced dose-dependent depletion of hepatic glutathione in mice, whereas phosphoramide mustard was at least one order of magnitude less effective. Acrolein caused death in mice; CP became covalently bound to hepatic macromolecules, prevented weight gain in rats, and produced hematuria and depression of hepatic cytochrome P-450 in vivo. These effects of CP (or acrolein) were enhanced by diethyl maleate but partially blocked by cysteine. On the other hand, reduction in the volume of Walker 256 carcinoma in rats by CP was not antagonized by cysteine. All these investigations point to the following conclusions: (a) acrolein produced during the metabolism of CP binds to proteins and, by doing so may denature these proteins; and (b) acrolein in vivo preferentially reacts with glutathione, and sulfhydryl-containing compounds may protect against acrolein toxicity and at the same time not interfere with the chemotherapeutic activity of CP.