THE GENOTOXICITY OF DIAVERIDINE AND TRIMETHOPRIM

We examined the genotoxicity of diaveridine and trimethoprim in the ba cterial umu test, the bacterial reverse mutation test, the in vitro ch romosome aberration test, the in vivo rodent bone marrow micronucleus test in two species, and the in vivo comet assay in five mouse organs. Both compounds were negative in the umu test (Salmonella typhimurium TA1535/pSK1002) and in the reverse mutation tests (S. typhimurium TA10 0, TA98, TA97, TA102, and Escherichia coli WP2 uvrA/pKM101) in the pre sence and absence of S9 mix. Diaveridine induced structural chromosome aberrations in cultured Chinese hamster CHL cells in the absence of a metabolic activation system, but not in the presence of a liver S9 fr action. No clastogenic activity in CHL cells was detected for trimetho prim. Bone marrow micronucleus tests in mice and rats conducted on dia veridine by single-and triple-oral dosing protocols were negative. The comet assay revealed that a single oral administration of diaveridine significantly induced DNA damage in liver, kidney, lung, and spleen c ells, but not in bone marrow cells. The significant increase in migrat ion values of DNA was reproducible with dose-response relationship. We suggest that the liver detoxifies the compound before it reaches the bone marrow, and that is why it is negative in the in vivo bone marrow micronucleus test. We concluded that diaveridine is genotoxic to mamm alian cells in vitro and in vivo. (C) 1997 Elsevier Science B.V.