STRUCTURAL AND MECHANISTIC BASES FOR THE INDUCTION OF MITOTIC CHROMOSOMAL LOSS AND DUPLICATION (MALSEGREGATION) IN THE YEAST SACCHAROMYCES-CEREVISIAE - RELEVANCE TO HUMAN CARCINOGENESIS AND DEVELOPMENTAL TOXICOLOGY

MultiCASE has the ability to automatically determine the structural fe atures responsible for the biological activity of chemicals. In the pr esent study, 93 chemicals tested for their ability to induce chromosom al 'malsegregation' in the yeast Saccharomyces cerevisiae were analyze d. This 'malsegregation' mimics molecular events that occur during hum an development and carcinogenesis resulting in an effective loss of on e chromosome of an autosomal pair and duplication of the homologue. St ructural features associated with the ability to induce such chromosom e loss and duplication were identified and compared with those obtaine d from examination of other toxicological data bases. The most signifi cant structural similarities were identified between the induction of chromosomal malsegregation and several toxicological phenomena such as cellular toxicity, induction of sister chromatid exchanges in vitro a nd rodent developmental toxicity. Very significant structural similari ties were also found with systemic toxicity, induction of micronuclei in vivo and human developmental toxicity. Less significant structural overlaps were found between yeast malsegregation and rodent carcinogen icity, DNA reactivity and mutagenicity, and the induction of chromosom e aberrations in vitro and sister chromatid exchanges in vivo. These o verlaps may indicate mechanistic similarities between the induction of chromosomal malsegregation and other toxicological phenomena. The pre dictivity of the SAR model derived from the present data base is relat ively low, however. This may be merely a reflection of the small size and composition of the data base, however, further analyses suggest th at it reflects primarily the multiple mechanisms responsible for the i nduction of chromosomal malsegregation in yeast and the complexity of the phenomenon.