Optimal dose selection of @entity7044 for the @entity35 comet assay to evaluate DNA damage in organs with different susceptibility to XXXX .

@entity35 @entity7045 @entity137 @entity7044
The in vivo rodent alkaline comet assay (comet assay) is a promising technique to evaluate DNA damage in vivo. However, there is no agreement on a method to evaluate DNA damage in organs where @entity137 is observed. As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the comet assay, we examined DNA damage in the liver, stomach, and bone marrow of @entity35 given three oral doses of @entity7044 ( @entity7045 ) up to the maximum tolerated dose based on systemic @entity137 . @entity7045 significantly increased the % tail DNA in all the organs. Histopathological analysis showed no cytotoxic effect on the liver, indicating clearly that @entity7045 has a genotoxic potential in the liver. In the stomach, however, the cytotoxic effects were very severe at systemically non-toxic doses. Low-dose @entity7045 significantly increased the % tail DNA even at a non-cytotoxic dose, indicating that @entity7045 has a genotoxic potential also in the stomach. Part of the DNA damage at cytotoxic doses was considered to be a secondary effect of severe cell damage. In the bone marrow, both the % tail DNA and incidence of micronucleated polychromatic erythrocytes significantly increased at non-hematotoxic doses, which were different from the non-cytotoxic doses for liver and stomach. These findings indicate that an optimal dose for detecting DNA damage may vary among organs and that careful attention is required to select an optimum dose for the comet assay based on systemic @entity137 such as mortality and clinical observations. The present study shows that when serious @entity137 is suggested by increased % hedgehogs in the comet assay, histopathological examination should be included for the evaluation of a positive response.
