Spontaneous renal tubular hyperplastic and neoplastic lesions in three Sprague-Dawley rats from a 90-day toxicity study.

Multiple renal tubular cell adenomas and atypical tubular hyperplasia were diagnosed in 2 high-dose and 1 mid-dose female Sprague-Dawley (Crl:CD (SD)IGS BR) rats from a 90-day toxicity study of an amino acid found in green tea. The tumors were bilateral multicentric adenomas accompanied by atypical foci of renal tubular hyperplasia in both kidneys of the 3 animals. Toxic tubular changes that typically accompany renal carcinogenesis were not seen in any of the other animals of the study, suggesting rather, an underlying germline mutation of a tumor suppressor gene in these three rats. The histological appearance of these tumors and short latency was reminiscent of the spontaneous lesions reported to arise in Sprague-Dawley rats in the Nihon rat model. Nihon rats develop kidney tumors as a result of a spontaneous mutation in the rat homologue of the Birt-Hogg-Dubé gene (Bhd). Frozen samples of liver from two tumor-bearing rats were assayed for germline alterations in the Bhd gene. The entire coding region (exons 3-13) of the Bhd gene was sequenced, and a guanine (nt106G) to adenine (nt106A) polymorphism was detected resulting in a glycine to arginine (G36R) substitution in both tumor-bearing animals. In the study animals, the frequency of the A-allele (adenine) was determined to be 27% (19/70). Interestingly, rats obtained from two other sources (n = 17) only carried the nt106G-allele, consistent with the published rat sequence for this gene. Genetic fingerprinting of microsatellite loci indicated that the rats had a shared genetic background. Laser capture microdissection (LCM) of the tumor cells demonstrated a loss of heterozygosity in the Bhd gene in neoplastic cells of one of the two animals. Taken together, these data suggest that the tumors observed in these animals arose spontaneously as a result of a shared genetic susceptibility leading to the development of renal tubular neoplasms.

Solid-state fluorescence studies of some polymorphs of diflunisal*.

PURPOSE: The solid-state luminescence spectroscopy of organic molecules is strongly affected by the effects of excited state energy transfer, with the fluorescence of solids often differing significantly from the fluorescence of the molecule dissolved in a solution phase. Because the magnitude of these solid-state effects is determined by the crystallography of the system, solid-state fluorescence studies can be used to gain insight into the polymorphism of the system. To this end, the spectroscopic properties of four polymorphs of diflunisal have been obtained, and compared to the properties of the molecule in the solution phase. METHODS: Fluorescence excitation and emission spectra were obtained on four polymorphic forms of diflunisal, and on the compound dissolved in water. RESULTS: It was found that exciton effects dominate the excitation spectra of diflunisal in the four studied polymorphic forms. These phenomena lead to a decrease in the energy of the excitation bands relative to that observed for the free molecule in fluid solution, and in a splitting of the excitation peak into two Davydov components. CONCLUSIONS: The trends in the excitation and emission spectra led to the grouping of diflunisal Forms I, II, and III into one category, and diflunisal Form IV into a separate category. Because other work has established that Form IV is characterized by the highest crystal density and consequent degree of intermolecular interaction, the magnitude of the exciton coupling can be used to estimate the degree of face-to-face overlap of the salicylate-type fluorophores.