title: Comparative quantitative structure toxicity relationships for flavonoids evaluated in isolated rat hepatocytes and HeLa tumor cells.
abstract: 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.
authors.affiliation: Faculty of Pharmacy, University of Toronto, 19 Russell Street, Ont., Toronto, Canada M5S 2S2.
authors.forename: Majid Y
authors.initials: MY
authors.lastname: Moridani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Galati
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Brien
mesh_terms: 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
chemical_list: D002109:Caffeic Acids; D005419:Flavonoids; D010636:Phenols; D011108:Polymers; D009637:Masoprocol; D011188:Potassium; D010693:Phloretin; C040048:caffeic acid