A structural analysis of the genotoxic and carcinogenic potentials of cyclosporin A.

The structural determinants identified by CASE, a knowledge-based structure--activity relational expert system, as contributing to toxicological effects have been distilled from the informational content of over 2000 molecules that have been adequately tested. This methodology has been applied to an analysis of the potential structural determinants of the mutagenicity, clastogenicity and carcinogenicity of cyclosporin A. The analysis predicts that cyclosporin A is devoid of mutagenicity, clastogenicity and DNA-modifying activity. There is however, a structural basis for its carcinogenicity in rodents, i.e. it appears to be a 'non-genotoxic' carcinogen. As a group, 'non-genotoxic' carcinogens are considered by some to pose a far lesser risk to humans than 'genotoxic' ones. The analysis is consistent with the interpretation that the carcinogenicity and immunosuppressive properties of cyclosporin A derive from different mechanisms and are, therefore, separable.