title: Studying significance of apoptosis in mediating tolbutamide-induced teratogenesis in vitro.
abstract: The incidence of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus) is growing worldwide and poses a serious public health problem in a current paradigm of changing life style and food habits. Tolbutamide (sulfonylurea) is among the commonly used anti-diabetic drugs worldwide for treating type 2 diabetes and is known to cause congenital malformations in animals. In this study, the effect of tolbutamide on major organogenesis period and the possible involvement of apoptosis in mediating congenital malformations have been carried out. In the present study design, post-implantation rat embryos of day 11 were cultured for 24 h with various concentrations of tolbutamide, i.e., 10, 100, and 1000 μg/mL cultures, respectively. The growth and developmental of each embryo was evaluated and compared with control ones for the presence of any malformations. The tolbutamide decreased all growth and developmental parameters in a concentration-dependent manner, when compared with control. However, exposure to tolbutamide at 10 μg/mL culture did not show any significant effect on embryonic growth and development in vitro. In parallel to this, flow cytometric analysis (cell cycle and annexin V binding) and DNA fragmentation assay were carried out followed by quantitation by 3'-OH labeling of cultured rat embryos to examine the role of apoptosis in bringing about tolbutamide-induced teratogenesis. All results were found to be dose dependent and an increase in apoptosis in embryonic tissues may be related to the increased risk of congenital malformations. The outcome of the research suggested that apoptosis might be involved in mediating teratogenesis of tolbutamide in vitro. Further research is warranted to fully understand this mechanism.
authors.affiliation: Division of Toxicology, Central Drug Research Institute, Lucknow 226001, India.
authors.forename: Gyanendra
authors.initials: G
authors.lastname: Singh
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Kumar
authors.forename: Neeraj
authors.initials: N
authors.lastname: Sinha
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects*; D004622:Embryo, Mammalian / Q000187:drug effects*; D009421:Nervous System Malformations / Q000139:chemically induced*; D051381:Rats; D014044:Tolbutamide / Q000009:adverse effects* / Q000494:pharmacology*
chemical_list: D004247:DNA; D014044:Tolbutamide