Carboxylesterases, a key factor in evaluating potential genotoxicity of Trinem antibiotics.
Sanfetrinem cilexetil, a hexetil ester of a Trinem antibiotic, does not induce micronuclei in rat bone marrow cells or induce DNA repair synthesis in rat hepatocytes following oral dosing. However, in vitro chromosome damage and mutations are induced in mammalian cells lacking carboxylesterase activity (human lymphocytes and mouse lymphoma L5178Y cells). In cells possessing carboxylesterase activity (CHL cells), chromosome damage induced by Sanfetrinem cilexetil is not observed. Similarly, if induced rat liver preparations or non-induced preparations from rat or human intestinal cells are present during exposure, genotoxic activity is lost, even in those cells lacking carboxylesterase enzymes. Thus the lack of demonstrable genotoxicity in vivo, in the assays used, is likely to be due to hydrolysis of the parent molecule by non-specific carboxylesterases present within the intestinal epithelium. In turn this data indicates that a genotoxic hazard to humans under therapeutic conditions is unlikely.
Oliver
J
J
Genetic Toxicology Department, Pre-Clinical Safety Sciences, Medicine Safety Evaluation Division, Glaxo Wellcome Research and Development, Park Road, Ware, Herts SG12 0DP, UK. jo3639@glaxowellcome.co.uk
Naidoo
A
A
Vandin
L
L
Pugnaghi
F
F
Gatehouse
D
D
Comelli
R
R
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D002265:Carboxylic Ester Hydrolases / Q000172:deficiency / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology; D007769:Lactams; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D009152:Mutagenicity Tests; D051381:Rats; D017208:Rats, Wistar
D000900:Anti-Bacterial Agents; D007769:Lactams; C114620:sanfetrinem cilexetil; D002265:Carboxylic Ester Hydrolases