Teratogenicity of three substituted 4-biphenyls in the rat as a result of the chemical breakdown and possible metabolism of a thromboxane A2-receptor blocker.
AH23848 is a potent thromboxane A2-receptor blocker inhibiting platelet aggregation in vitro and in vivo. Oral administration to pregnant rats during days 7-16 of pregnancy, at doses of 0, 10, 45, or 200 mg/kg twice daily, resulted in dose-related maternal, embryonic, and fetal toxicity. The most notable observation was herniation of the diaphragm occurring in 1.5 and 100.0% of fetuses at the 45 and 200 mg/kg doses, respectively, when examined at term. A further study at 150 mg/kg twice daily during days 7-16, 7-11, or 12-16 of pregnancy revealed incidences of diaphragmatic hernia up to 42%. Herniation varied from small areas of eventration of membranous diaphragm to fetuses with apparent total absence of the diaphragm. The positions of the hernias in the diaphragm, following dosing over varying periods of organogenesis, reflected the chronology of diaphragm formation in the rat. The teratology of AH23848 was unrelated to its thromboxane A2-receptor blocker properties but was related to a chemical breakdown product, 4-biphenylmethanol. Some substituted biphenyl compounds appear to be specific teratogens in the rat, with their effects targeted at the developing diaphragm. A possible mechanism of herniation is the interference with muscularisation of the membranous diaphragm, resulting in weakness and perforation.
Sutherland
M F
MF
Genetic and Reproductive Toxicology Department, Glaxo Group Research Ltd., Ware, Hertfordshire, England.
Parkinson
M M
MM
Hallett
P
P
D000284:Administration, Oral; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005865:Gestational Age; D006548:Hernia, Diaphragmatic / Q000139:chemically induced* / Q000196:embryology; D006863:Hydrogen-Ion Concentration; D015394:Molecular Structure; D009024:Morphogenesis; D011247:Pregnancy; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism*; D017482:Receptors, Thromboxane; D013723:Teratogens; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
D001713:Biphenyl Compounds; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013723:Teratogens; D013931:Thromboxanes; C060879:GR 36246; C046926:AH 23848