Comparative embryotoxicity of four anthracyclines: In Vitro study on their effects on glutathione status

The embryotoxicity of four different anthracyclines [doxorubicin (DOXO), epirubicin (EPI), daunorubicin (DAUNO) and idarubicin (IDA)] was compared using the postimplantation whole embryo culture method. Moreover, to investigate the role of free oxygen radical production in anthracycline-induced embryotoxicity, the reduced glutathione (GSH) status in embryos and extraembryonic membranes was measured. Rat embryos (1-3 somite stage) were cultured for 48 hr in heat-inactivated rat serum containing DOXO, EPI or DAUNO (0.025, 0.05, 0.075 or 0.1 muM) or IDA (0.0125, 0.025 or 0.05 muM). At the end of the culture period, the embryos were examined morphologically and processed for histological or biochemical examination. DOXO, EPI and DAUNO were found to have similar embryotoxic potential [the no-observed-effect level (NOEL) was 0.025 muM], whereas IDA had a greater effect (NOEL = 0.0125 muM). The primary target organ was identified macroscopically and microscopically for all compounds in the mesenchyme of the caudal region. No relationship was identified between embryonic or extraembryonic GSH content reduction and anthracycline-induced embryotoxicity, suggesting only a marginal role of free oxygen radical formation in anthracycline-related embryotoxic mechanisms.