Structure–activity Relationships for Pimephales and Tetrahymena: A Mechanism of Action Approach

Abstract

Abstract-The toxicity data of 74 chemicals tested in both the 96-h fathead minnow (Pimephales promelas) mortality assay and the 2-d Tetrahymena pyriformis (a protozoan) growth inhibition assay were evaluated using quantitative structure-activity relationships (QSARs). Each chemical was a priori assigned a mechanism of acute toxic action from either nonpolar narcosis, polar narcosis, weak acid respiratory uncoupling, soft electrophilicity, or proelectrophilicity. The polar narcotics were further split into a phenol group and an aniline group. The relationship between bioreactivity and the importance of penetration to the site of action in both systems was studied. Bioreactivity showed a trend to be inversely proportional to the value of the hydrophobicity term. The data were examined to investigate how different molecular descriptors modeled the mechanisms of action. Models were produced for nonpolar narcotics and anilines for both species with the 1-octanol/water partition coefficient (log K ow ) alone. Soft electrophiles were best predicted by the average acceptor superdelocalizability ( ), whereas proelectrophiles were modeled by log K ow and n S av . The weak acid uncouplers modeled with either log K ow or log K ow plus the ionization constant (pK a ) for Pimephales and n S av Tetrahymena, respectively. Phenols yielded predictive models using a either a combination of log K ow with or lowest unoccupied n S av molecular orbital, for fathead minnow and protozoan, respectively.

Quantitative Structure-Activity Relationships for the Toxicity to the Tadpole Rana japonica of Selected Phenols

“…LogK ow , dependent QSAR models are often developed to study the different mechanisms of toxic action of chemicals (Schultz et al 1986, Bearden andSchultz 1997). Polar narcosis has proved to be the main mechanism for most substituted phenols, including alkyl and alkoxyl substituted, mono-and di-halogen substituted phenols, etc (Schultz et al 1989(Schultz et al , 1992.…”

“…4-Cl-2-nitrophenol might act as a weak acid respiratory uncoupler as its molecular structure features similar to weak acid respiratory uncouplers: (1) there is a moderately weak acid moiety (hydroxy1 group) on a bulky and hydrophobic aromatic ring system; (2) with additional electron-withdrawing substituents: a chloro group and a nitro group; (3) with a pKa value (6.48) close to the intramitochondrial pH value (Schultz et al 1990a). 4-Nitrophenol has been regarded as a pro-electrophile in other test systems including E. coli, Tetrahymena pyriformis and Pimephales promelas (Jaworska and Schultz 1994;Cronin and Schultz et al 1996;Bearden and Schultz 1997). The molecular structure of salicylaldehyde is very similar to an α,β-unsaturated compound because its carbonyl group is conjugated with aromatic double bonds.…”

“…Comparative studies were performed on the mechanisms of toxicity of phenols to Pimephales promelas and to Tetrahymena pyriformis by Schultz et al (1986) and Bearden et al (1997). Polar narcosis and/or uncoupling of weak acid respiratory mechanisms were found to be main mechanisms for most phenols.…”

Impact of Orthogonal Signal Correction (OSC) on the Predictive Ability of CoMFA Models for the Ciliate Toxicity of Nitrobenzenes Dedicated to Professor Werner Klein, Schmallenberg (Germany), on the oaccastion of his 65th birthday

“…Group1 consisted of the compounds #1, 2,4,8,11,14,17,19,21,22,23,24,25,29,31,32,33,36,37,41,44,46 and 47 (numbering according to Table 1), thus including five (out of 12) ortho compounds, eight (out of 14) meta compounds, nine (out of 20) para compounds and nitrobenzene. For simulating external validation, the compounds were temporarily re-numbered according to decreasing toxicity, and then subdivided into the groups of odd-numbered (group1) and even-numbered (group2) compounds (referring to the toxicity-ordered numbering).…”

Use of Molecular Descriptors in Separating Phenols by Three Mechanisms of Toxic Action

“…Second, MOAs are sensitive to changes in the substructure since very small changes may lead to a completely different MOA [17]. Third, compounds having the same substructures can be associated with several MOAs [8,18], as is the case for phenols. Fourth, assigning a MOA to a compound is made more complicated and less reliable as the number of characteristic substructures in a molecule increases.…”