The present study investigated the teratogenicity of the oral
hypoglycemic agent,
tolbutamide, using an in vitro approach, and evaluated the role of its main metabolic effect,
hypoglycemia.
Teratogenesis was evaluated by culturing early-somite mouse embryos for 24 h in serum from rats treated with
tolbutamide (79-117 micrograms/ml) or normal rat serum supplemented with
tolbutamide (110-152 micrograms/ml).
Tolbutamide-treated serum was then supplemented with
glucose to control for potential effects of
hypoglycemia. Mouse embryos demonstrated high malformation rates following exposure to serum from
tolbutamide-treated rats (79%) or normal rat serum supplemented with
tolbutamide (85%) compared with controls (4%), and defects included cardiac, ocular, neural tube, and somite abnormalities. Overall growth was reduced in treated embryos and yolk sacs, as determined by total
protein contents. Embryonic growth and malformation rates were not improved by
glucose supplementation of
hypoglycemic tolbutamide-treated serum. Thus,
tolbutamide produces malformation in mouse embryos in vitro at concentrations comparable to those in human serum, and the effects do not appear to be mediated by
hypoglycemia. The potential risk of
tolbutamide on the developing embryo must be considered in the
therapy of pregnant diabetic patients.