THE ROLE OF OXYGENATION IN EMBRYOTOXIC MECHANISMS OF 3 BIOREDUCIBLE AGENTS

Many xenobiotics used in the treatment of hypoxic pathogens and tumors require reductive bioactivation under anaerobic conditions for maximal effectiveness and/or toxicity. A number of agents of this type have been shown to be teratogenic in vitro and/or in vivo. Early conceptuses may be vulnerable to these agents because they exist in a relatively anaerobic environment and have the capacity to perform reductive metabolism. It has been hypothesized that the single electron redox potential of bioreducible agents plays a dominant role in the capacity to induce anomalies. We examined the in vitro embryotoxicity in rats of three bioreducible drugs of similar redox potential under normoxic and hypoxic conditions as well as the capacity of those drugs to redox cycle and to damage DNA in embryonic tissue. Adriamycin, mitomycin C, and niridazole were shown to have differential embryotoxic responses in vitro to altered oxygenation. Studies of the bases of drug action showed (1) Adriamycin induces DNA strand breaks at concentrations that correlate well with embryolethality; (2) Mitomycin C does not induce strand breaks, but its dysmorphogenicity is increased by hypoxia; and (3) Niridazole does not produce DNA damage but appears to induce asymmetric malformations by depleting embryonic oxygen through redox cycling. Together the studies show that dysmorphogenic and embryolethal effects may result from separate mechanisms and that oxygenation plays an important role in those mechanisms.