Embryotoxicity elicited by inhibition of gamma-glutamyltransferase by Acivicin and transferase antibodies in cultured rat embryos.
Acivicin (also known as AT-125) and IgG isolated from goat anti-gamma-glutamyltransferase antiserum were used to inhibit the activity of gamma-glutamyltransferase (GGT, EC 2.3.2.2) in rat conceptuses cultured from Days 10 to 11 of gestation. Inhibition of GGT by either Acivicin or anti-GGT IgG produced embryotoxicity and malformations, although each compound produced a unique spectrum of effects. Acivicin, at an initial concentration in the culture medium of 5 microM, produced a marked decrease in yolk sac vasculature and was associated with embryonic malformations such as neural tube necrosis, microophthalmia, and cephalic edema after 24 hr exposure. These malformations were accompanied by significant decreases in both embryonic and yolk sac protein, yolk sac GGT activity, as well as embryonic glutathione (GSH) levels. In contrast, anti-GGT IgG produced no apparent effects on yolk sac vasculature or protein after exposure of conceptuses to an initial concentration of 50 micrograms IgG/ml culture medium, even though equal inhibition of yolk sac GGT (30%) was achieved by each inhibitor. Exposure to IgG (50 micrograms/ml) for 24 hr was associated with decreased embryonic protein; decreased levels of GSH in the embryo were observed after both 3 and 24 hr. The dichotomy of effects on the yolk sac by the two compounds indicates that Acivicin produced these effects by mechanisms other than by GGT inhibition alone. These results demonstrate that inhibition of GGT in rat embryos undergoing organogenesis can elicit embryotoxic effects and produce alterations in GSH levels. The capacity of the anti-GGT antibody to inhibit the GGT activity in the yolk sac (while having no apparent effect on yolk sac morphology), and yet influence the embryo by decreasing protein and GSH levels, underscores the important role of the yolk sac during the highly sensitive stages of organogenesis.
D000818:Animals; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000201:enzymology; D007074:Immunoglobulin G / Q000276:immunology*; D007555:Isoxazoles / Q000633:toxicity*; D009924:Organ Culture Techniques; D010080:Oxazoles / Q000633:toxicity*; D011506:Proteins / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D005723:gamma-Glutamyltransferase / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000276:immunology
D007074:Immunoglobulin G; D007555:Isoxazoles; D010080:Oxazoles; D011506:Proteins; D005723:gamma-Glutamyltransferase; C006303:acivicin