Comparative quantitative structure toxicity relationships for flavonoids evaluated in isolated rat hepatocytes and HeLa tumor cells.
Quantitative structure activity relationship (QSAR) equations were obtained to describe the cytotoxicity of 22 polyphenols using toxicity (logLD50) representing the concentration for 50% cell survival in 2 h for isolated rat hepatocytes, log P representing octanol/water partitioning, and/or E(p/2) representing redox potential. One- and two-parameter equations were derived for the quantitative structure toxicity relationships (QSTR) for polyphenol induced hepatocyte cytotoxicity: e.g. log C(hepatocyte) (microM)=-0.65(-0.08)log P+4.12(-0.15) (n=19, r(2)=0.80, s=0.33, P<1 x 10(-6)). One- and two-parameter QSAR equations were also derived to describe the inhibitory effects of 13 polyphenols on tumor cell growth when incubated with HeLa cells for 3 days: e.g. log C(tumor) (microM)=-0.34(+/-0.04)log P+2.40(+/-0.07) (n=11, r(2)=0.90, s=0.13, P<1 x 10(-5)). These findings point to lipophilicity as a major characteristic determining polyphenol cytotoxicity. The E(p/2) also played a significant role in polyphenol cytotoxicity towards both cell types: e.g. log C(hepatocyte) (microM)=-0.60(+/-0.06)log P+2.01(+/-0.43)E(p/2) (V)+3.86(+/-0.12) (n=9, r(2)=0.96, s=0.15, P<0.005). The involvement of log P and E(p/2) could be explained if polyphenol cytotoxicity involved the formation of radicals, which interacted with the mitochondrial inner membrane resulting in a disruption of the membrane potential.
Moridani
Majid Y
MY
Faculty of Pharmacy, University of Toronto, 19 Russell Street, Ont., Toronto, Canada M5S 2S2.
Galati
Giuseppe
G
O'Brien
Peter J
PJ
D000818:Animals; D002109:Caffeic Acids / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects*; D005419:Flavonoids / Q000633:toxicity*; D006367:HeLa Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D009637:Masoprocol / Q000633:toxicity; D008954:Models, Biological; D010636:Phenols / Q000633:toxicity*; D010693:Phloretin / Q000633:toxicity; D011108:Polymers / Q000633:toxicity*; D011188:Potassium / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D012044:Regression Analysis
D002109:Caffeic Acids; D005419:Flavonoids; D010636:Phenols; D011108:Polymers; D009637:Masoprocol; D011188:Potassium; D010693:Phloretin; C040048:caffeic acid