An examination of quinone toxicity using the yeast Saccharomyces cerevisiae model system.
The toxicity of quinones is generally thought to occur by two mechanisms: the formation of covalent bonds with biological molecules by Michael addition chemistry and the catalytic reduction of oxygen to superoxide and other reactive oxygen species (ROS) (redox cycling). In an effort to distinguish between these general mechanisms of toxicity, we have examined the toxicity of five quinones to yeast cells as measured by their ability to reduce growth rate. Yeast cells can grow in the presence and absence of oxygen and this feature was used to evaluate the role of redox cycling in the toxicity of each quinone. Furthermore, yeast mutants deficient in superoxide dismutase (SOD) activity were used to assess the role of this antioxidant enzyme in protecting cells against quinone-induced reactive oxygen toxicity. The effects of different quinones under different conditions of exposure were compared using IC50 values (the concentration of quinone required to inhibit growth rate by 50%). For the most part, the results are consistent with the chemical properties of each quinone with the exception of 9,10-phenanthrenequinone (9,10-PQ). This quinone, which is not an electrophile, exhibited an unexpected toxicity under anaerobic conditions. Further examination revealed a potent induction of cell viability loss which poorly correlated with decreases in the GSH/2GSSG ratio but highly correlated (r2 > 0.7) with inhibition of the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), suggesting disruption of glycolysis by this quinone. Together, these observations suggest an unexpected oxygen-independent mechanism in the toxicity of 9,10-phenanthrenequinone.
Department of Pharmacology, UCLA School of Medicine, Center for the Health Sciences, Los Angeles, CA 90095-1735, USA.
Chester E
CE
Rodriguez
Masaru
M
Shinyashiki
John
J
Froines
Rong Chun
RC
Yu
Jon M
JM
Fukuto
Arthur K
AK
Cho
D002470:Cell Survival / Q000187:drug effects; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction / Q000187:drug effects; D010616:Phenanthrenes / Q000633:toxicity; D011809:Quinones / Q000633:toxicity*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship
D010616:Phenanthrenes; D011809:Quinones; C005399:9,10-phenanthrenequinone; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases