ABSTRACT
Preclinical safety studies with the leukotriene D4 antagonist RG 12525 were conducted by the oral route in mice, rats, and monkeys. Oral administration of RG 12525 was repeated daily in studies up to 6 months in duration. RG 12525 was shown to have limited high-dose toxicity after repeated oral administration. The effects of RG 12525 were strongly dependent upon the species considered. High doses of RG 12525 caused significant increases in liver weight in mice, rats, and monkeys that were associated with diffuse hepatocellular hypertrophy in mice and rats but not in monkeys. No related clinical chemistry changes were observed in any of the species and hepatic activities of peroxisomal enzymes or cytochrome P450 were increased only slightly. Proliferation of brown adipose tissue (BAT) was observed in rats and mice but not in monkeys. The BAT reaction was more pronounced in the interscapular area but it was also observed in other subcutaneous locations as well as in mediastinal and bone marrow fat. In all locations, the RG 12525-induced BAT had some morphological similarities with cold-adapted BAT. Repeated administration of RG 12525 at high doses to female rats resulted in a lack of progression to the luteal phase of the estrous cycle that was reversible after discontinuation of treatment. Finally, RG 12525 was nephrotoxic in mice with males being more sensitive than females.
Subject(s)
Leukotriene D4/antagonists & inhibitors , Quinolines/toxicity , Tetrazoles/toxicity , Animals , Corpus Luteum/drug effects , Eating/drug effects , Erythrocyte Count/drug effects , Estrus/drug effects , Female , Hematocrit , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Liver/drug effects , Liver/pathology , Macaca mulatta , Male , Mice , Mice, Inbred ICR , Microbodies/drug effects , Microbodies/metabolism , Organ Size/drug effects , Rats , Rats, Sprague-Dawley , Sex Characteristics , Weight Gain/drug effectsABSTRACT
This study was performed to investigate the potential effects of nocturnal, low-intensity light upon ovarian morphology of female Sprague-Dawley rats and to investigate the cause for ovarian changes which had been observed in an earlier study following transient exposure of control female Sprague-Dawley rats to indirect light of minimal intensity during the nocturnal 12-h dark cycle. Twenty female Sprague-Dawley CD rats (initial age: 5 weeks) were kept for 8 weeks under our standard laboratory conditions including a daily 12-h light cycle (light intensity: approximately 200 lux) followed by a 12-h dark cycle with exposure to an indirect light source of low intensity (approximately 30 lux). Ten female control rats of comparable age from a concurrent toxicology study housed in an adjacent animal room under our standard 12 h light/dark cycle served as controls. At the end of the study the rats were sacrificed, necropsied and the ovaries were evaluated histopathologically. In 5 of the 20 animals we found ovarian atrophy consisting of decreased number and size of corpora lutea and increased number of tertiary follicles and/or follicular cysts. Most corpora lutea present in these ovaries were old, indicating the absence of recent ovulations. In contrast, the incidence of ovarian changes in the control group was 0/10. In conclusion, nocturnal exposure of female Sprague-Dawley rats to light of minimal intensity produced a substantial incidence of ovarian changes and suggests that the incidence of ovarian atrophy observed in a previous study may have been due to transient exposure to indirect nocturnal light of minimal intensity.
