Xenobiotic metabolism in the isolated conceptus.
The development of culture systems using either pre- or post-implantation embryos has made it possible to study the metabolizing capacity of the isolated conceptus in vitro. In the rodent pre-implantation embryo and post-implantation conceptus (embryo and its membranes), constitutive levels and inducibility of different enzyme systems involved in drug metabolism have been shown in vitro to lead to the formation of embryotoxic metabolites of different xenobiotics. This indicated the presence of enzyme systems during early organogenesis. For example, using the rat post-implantation embryo culture, we could show that incubation with the lipoxygenase inhibitor N-hydroxy-N-methyl-7-propoxy-2-naphthalenethanamine (QAB) led to high levels of the main in vivo metabolite 7-propoxy-naphthalene-2-ylacetic acid (QAA) and two as yet unidentified products, M5 and M6, in the conceptus. QAB was not found in tissues and QAA itself did not enter the embryonic compartments. In addition, accumulation in tissue was dependent on the time and duration of exposure. It started at 10.5 days of development. A similar metabolite pattern was obtained after yolk-sac tissue had been cultured alone, which suggests metabolizing capacity of mainly the yolk-sac tissue. The enzyme reactions involved might have included oxidative N-demethylation and oxidative deamination, probably also including the formation of reactive intermediate metabolites. In conclusion, our data demonstrate that not only maternal metabolism may play an important role in the toxic action of xenobiotics, but also the metabolizing capacity of the conceptus itself may be crucial, since the formation of (intermediate, highly reactive) metabolites takes place at the target site.
Bechter
R
R
Toxicology Department, Drug Safety Assessment, Sandoz Ltd, CH-4002, Basle, Switzerland.
Terlouw
G D
GD