Tapetal changes in beagle dogs following oral administration of CGS 14796C, a potential aromatase inhibitor

Abstract

CGS 14796C, cis-1-[(4-[(1-imidazolyl)methyl]-cyclohexyl)methyl)imidazole succinate, has been evaluated as a potential aromatase inhibitor. As part of the safety evaluation program, a 3-month oral toxicity study was performed in which beagle dogs were administered CGS 14796C by gavage at 5, 15, or 50 mg/kg/day. Ophthalmoscopically, changes in the tapetum lucidum affecting dogs from the 15 and 50 mg/kg dose levels were diffuse areas of pigmentation varying in appearance from a brownish peppered or mottled to a more uniform brown similar to that of the nontapetal area of the fundus. Tapetal reflectivity was absent or markedly reduced. Within the pigmented area, multiple islets (yellow, green, or organe) of tapetal cells were visible, suggestive of destruction of the tapetum. In no instance was retinal destruction, edema, vascular changes, or detachment observed. Ophthalmoscopic examinations performed during recovery revealed changes of slight increase in tapetal islets, suggestive of a slight progression and organization within the tapetum followed by an arrest of the toxic insult within the tapetal tissue. At light and electron microscopic examination of the ocular tissues, the lesions were tapetal cell degeneration/atrophy. These results demonstrated that the taptetum lucidum was a target tissue of toxicity for CGS 14796C, and indicated that the findings are without toxicological significance in atapetal species, including man, whose globes do not have this structure.