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Carboxylesterases, a key factor in evaluating potential genotoxicity of Trinem antibiotics
1Genetic 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
Abstract:
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.
Insights
Sanfetrinem cilexetil, a Trinem antibiotic, did not show genotoxicity in vivo. The drug is unlikely to pose a genotoxic hazard to humans during therapeutic use due to its rapid hydrolysis.
Area of Science:
- Pharmacology
- Toxicology
- Genetics
Background:
- Sanfetrinem cilexetil is a Trinem antibiotic hexetil ester.
- Assessing the genotoxic potential of pharmaceuticals is crucial for drug safety.
Purpose of the Study:
- To evaluate the in vivo and in vitro genotoxicity of Sanfetrinem cilexetil.
- To investigate the role of carboxylesterase activity in the genotoxic profile of Sanfetrinem cilexetil.
Main Methods:
- In vivo micronucleus test in rat bone marrow.
- In vivo DNA repair synthesis assay in rat hepatocytes.
- In vitro chromosomal aberration and mutation assays in mammalian cells with and without carboxylesterase activity.
- In vitro assays with rat liver and intestinal preparations.
Main Results:
- Sanfetrinem cilexetil did not induce genotoxicity in vivo in rats.
- In vitro, chromosome damage and mutations were observed in cells lacking carboxylesterase activity.
- Genotoxicity was abolished in the presence of carboxylesterase activity (CHL cells) or esterase preparations from rat liver and intestinal cells.
Conclusions:
- The lack of in vivo genotoxicity is attributed to rapid hydrolysis by intestinal carboxylesterases.
- Sanfetrinem cilexetil is unlikely to present a genotoxic hazard to humans under therapeutic conditions.