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Effects of some sugar alcohol derivatives on mutation and induction of sister chromatid exchanges
Abstract:
The mutagenicity of various alkylating sugar alcohol derivatives in the Salmonella-microsome assay was studied, and the effects of these compounds on the colony-forming ability and the frequency of sister chromatid exchange (SCE) in Chinese hamster cells were determined. Cytostatic drugs under clinical trial [Elobromol (DBD), Myelobromol (DBM), Lycurim (LY), Zitostop (ZI)], others in preclinical analysis [dianhydrogalactitol (DAG), 3,4-diacetyldianhydrogalactitol (DiacDAG), 3,4-disuccinyldianhydrogalactitol (DisuDAG)], and compounds without any known antitumor effect in transplantable tumors [1-bromo-3,6-anhydrodulcitol (BAD), 1,2-epoxi-3,6-anhydrodulcitol (EAD)] were examined. All the tested compounds except DisuDAG were directly mutagenic in Salmonella strains TA 1535 and TA 100. The mutagenic effect of the chemicals was not influenced by S9 mix from rat liver, with the exception of ZI and DiacDAG. DisuDAG appeared nonmutagenic in strains TA 1535 and TA 100 exposed to microsomal enzymes from rat liver, lung, and kidney and mouse and hamster liver, nor was DisuDAG mutagenic in strains TA 1537, TA 1538, and TA 98 in either the presence or the absence of rat liver S9 mix. Mouse urine, after a single administration of DisuDAG to the animal, proved to be mutagenic in strain TA 1535. This effect can be attributed to the presence of DAG and EAD which could be identified by thin-layer chromatography of urine, thus establishing the premutagenic character of DisuDAG. All sugar alcohol derivatives increased the frequency of SCE. Doses required to double the control SCE frequency were in the sublethal range of the survival curve for DBD, DBM, LY, DAG, and DiacDAG. Doses higher than the sublethal ones were required of ZI, DisuDAG, BAD, and EAD to achieve a 2-fold increase in SCE frequency. On the basis of these doses, the relative potencies for SCE induction of the compounds were as follows: EAD less than BAD less than DisuDAG less than ZI less than DiacDAG less than DAG less than DBD less than DBM less than LY. Within this range, there was a 2 million-fold difference in the SCE production of these chemically related compounds.
Insights
This study investigated the mutagenicity and genotoxicity of sugar alcohol derivatives, finding most were mutagenic and induced sister chromatid exchange (SCE). Notably, 3,4-disuccinyldianhydrogalactitol (DisuDAG) showed premutagenic potential, converting to active mutagens in vivo.
Area of Science:
- Chemical Mutagenesis and Genotoxicity
- Drug Development and Toxicology
- Biochemistry and Molecular Biology
Background:
- Sugar alcohol derivatives are explored for potential therapeutic applications, necessitating a thorough understanding of their genotoxic profiles.
- Assessing the mutagenicity and clastogenicity of novel chemical entities is crucial for safety evaluation.
- The Salmonella-microsome assay and sister chromatid exchange (SCE) assay are standard methods for evaluating genotoxicity.
Purpose of the Study:
- To evaluate the mutagenicity of various alkylating sugar alcohol derivatives using the Salmonella-microsome assay.
- To determine the effects of these compounds on colony-forming ability and SCE frequency in Chinese hamster cells.
- To investigate the premutagenic potential of 3,4-disuccinyldianhydrogalactitol (DisuDAG).
Main Methods:
- Salmonella-microsome assay (Ames test) with Salmonella strains TA 1535, TA 100, TA 1537, TA 1538, and TA 98, with and without rat liver S9 mix.
- Assessment of colony-forming ability and sister chromatid exchange (SCE) frequency in Chinese hamster cells.
- Thin-layer chromatography for identifying metabolites in mouse urine after DisuDAG administration.
Main Results:
- Most tested sugar alcohol derivatives, except DisuDAG, were directly mutagenic in Salmonella strains TA 1535 and TA 100.
- DisuDAG exhibited premutagenic activity, with its metabolites (dianhydrogalactitol and epoxi-anhydrodulcitol) identified in mouse urine.
- All derivatives increased SCE frequency in Chinese hamster cells, with significant variations in potency, spanning a 2 million-fold range.
Conclusions:
- Several alkylating sugar alcohol derivatives possess mutagenic and genotoxic properties.
- DisuDAG is a premutagen, requiring metabolic activation to exert its mutagenic effects.
- The study highlights significant differences in genotoxic potency among chemically related sugar alcohol derivatives, crucial for risk assessment.