Genetic toxicity evaluation of McN-5195: a novel analgesic.
McN-5195, (+/-)-trans-3-(2-bromophenyl)octahydroindolizine, a novel analgesic, was tested for genotoxic potential in a battery of tests with endpoints of mutagenicity, chromosomal alterations and DNA damage/repair. McN-5195 was not mutagenic when tested in the Ames test using strains TA98, TA100, TA1535, TA1537 and TA1538, in the absence of metabolic activation and in the presence of Aroclor 1254-induced rat or hamster S-9. Negative results were also obtained in the mouse lymphoma assay in the absence of activation, but reproducible mutagenic responses were seen in this mammalian cell assay in the presence of rat S-9 at high levels of induced toxicity (reduced cell growth). Testing of the enantiomers of McN-5195 in this assay supported these findings. A predominance of small mutant colonies in the mouse lymphoma assay suggested a potential chromosomal effect of McN-5195. This was confirmed with positive findings in an in vitro cytogenetics assay using CHO cells, again at toxic exposure levels and only in the presence of S-9. McN-5195 did not induce DNA repair in the primary rat hepatocyte/DNA repair assay, nor did it induce alterations in vivo of chromosome structure or number when tested in a rat bone marrow cytogenetics assay. The findings from this battery of tests indicate that McN-5195 has modest genotoxic activity when tested in the presence of rat liver S-9 in in vitro systems sensitive to cytogenetic change. The absence of genotoxicity in vitro in Salmonella and intact liver cells and in vivo in rat bone marrow suggests that McN-5195 is unlikely to present a genotoxic risk to whole animals.
Oldham
J W
JW
Department of Toxicology, McNeil Pharmaceutical, Spring House, Pennsylvania 19477.
Sedor
D D
DD
Preston
R F
RF
Newman
D
D
Paulson
J D
JD
D000700:Analgesics / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002875:Chromosomes / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D007212:Indolizines / Q000633:toxicity*; D008099:Liver / Q000166:cytology; D051379:Mice; D009152:Mutagenicity Tests; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects
D000700:Analgesics; D007212:Indolizines; C058653:3-(2-bromophenyl)octahydroindolizine