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 features responsible for the biological activity of chemicals. In the present study, 93 chemicals tested for their ability to induce chromosomal 'malsegregation' in the yeast Saccharomyces cerevisiae were analyzed. This 'malsegregation' mimics molecular events that occur during human development and carcinogenesis resulting in an effective loss of one chromosome of an autosomal pair and duplication of the homologue. Structural features associated with the ability to induce such chromosome loss and duplication were identified and compared with those obtained from examination of other toxicological data bases. The most significant 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 and rodent developmental toxicity. Very significant structural similarities 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 carcinogenicity, DNA reactivity and mutagenicity, and the induction of chromosome aberrations in vitro and sister chromatid exchanges in vivo. These overlaps may indicate mechanistic similarities between the induction of chromosomal malsegregation and other toxicological phenomena. The predictivity of the SAR model derived from the present data base is relatively low, however. This may be merely a reflection of the small size and composition of the data base, however, further analyses suggest that it reflects primarily the multiple mechanisms responsible for the induction of chromosomal malsegregation in yeast and the complexity of the phenomenon.
Liu
M
M
Department of Environmental and Occupational Health, University of Pittsburgh, PA 15238, USA.
Grant
S G
SG
Macina
O T
OT
Klopman
G
G
Rosenkranz
H S
HS
D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity*; D002869:Chromosome Aberrations; D015825:Chromosomes, Fungal / Q000235:genetics*; D016208:Databases, Factual; D005819:Genetic Markers; D006801:Humans; D008938:Mitosis; D008957:Models, Genetic; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D012486:Salmonella typhimurium / Q000235:genetics; D013329:Structure-Activity Relationship
D002273:Carcinogens; D005819:Genetic Markers; D009153:Mutagens