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.