title: Quantitative structure toxicity relationships for catechols in isolated rat hepatocytes.
abstract: One- and two-parameter quantitative structure toxicity relationship (QSTR) equations were obtained to describe the cytotoxicity of isolated rat hepatocytes induced by 23 catechols in which LD(50) represents the catechol concentration required to induce 50% cytotoxicity in 2 h. A QSTR equation logLD(50) (microM = - 0.464(+/-0.065) log P + 3.724(+/-0.114) (n = 20, r(2) = 0.740, s(y,x) = 0.372, P < 1 x 10(-6), outliers: 4-methoxycatechol, 3-methoxycatechol, L-dopa) was derived where logP represents octanol/water partitioning. Outliers were determined by adopting a statistical method to standardize the identification of outliers. When pK(a1), the first ionization constant, was considered as a contributing parameter a two-parameter QSTR equation was derived: logLD(50) (microM = - 0.343(+/-0.058) log P - 0.116(+/-0.041) pK(a1)+4.389 (+/-0.315) (n = 22, r(2) = 0.738, s(y,x) = 0.375, P < 0.01, outlier: 4-methoxycatechol). Replacing logP with logD(7.4), the partition coefficient at pH 7.4, improved the first correlation by limiting the outlier to 4-methoxycatechol: logLD(50) (microM)=-0.252(+/-0.039) logD(7.4)+3.168(+/-0.090) (n = 22, r(2) = 0.671, s(y,x) = 0.420, P < 1 x 10(-5). In this study, 4-methoxycatechol (readily autooxidizable) was found to be an outlier for all QSTR equations derived. These findings point to lipophilicity and pK(a1) as two important characteristics of catechols that can be used to predict their cytotoxicity towards isolated rat hepatocytes. The catechols with the higher lipophilicity/distribution coefficient, the lower degree of ionization and the higher pK(a(catechol)) were more toxic towards hepatocytes than the other catechols.
authors.affiliation: Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ont., Canada M5S 2S2.
authors.forename: Majid Y
authors.initials: MY
authors.lastname: Moridani
authors.forename: Arno
authors.initials: A
authors.lastname: Siraki
authors.forename: Tatiana
authors.initials: T
authors.lastname: Chevaldina
authors.forename: Hugh
authors.initials: H
authors.lastname: Scobie
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D002396:Catechols / Q000737:chemistry / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008297:Male; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D002396:Catechols