A Mechanistic Structure-Activity Relationship for Hepatic Polysubstrate Monooxygenase

440

401

Abstract-In the field of aquatic toxicology, quantitative structure-activity relationships (QSARs) have developed as scientifically credible models for predicting the toxicity of chemicals when little or no empirical data are available. In recent years, there has been an evolution of QSAR development and application from that of a chemical-class perspective to one that is more consistent with assumptions regarding modes of toxic action. The objective of this research was to develop procedures that relate modes of acute toxic action in the fathead minnow (Pimephales promelas) to chemical structures and properties. An empirically derived database for diverse chemical structures of acute toxicity and corresponding modes of toxic action was developed through joint toxic action studies, the establishment of toxicodynamic profiles, and behavioral and dose-response interpretation of 96-h LC50 tests. Using the results from these efforts, as well as principles in the toxicological literature, approximately 600 chemicals were classified as narcotics (three distinct groups), oxidative phosphorylation uncouplers, respiratory inhibitors, electrophiles/proelectrophiles, acetylcholinesterase inhibitors, or central nervous system seizure agents. Using this data set, a computer-based expert system has been established whereby chemical structures are associated with likely modes of toxic action and, when available, corresponding QSARs.

Section: Discussionmentioning

confidence: 99%

Predicting modes of toxic action from chemical structure: Acute toxicity in the fathead minnow (Pimephales promelas)

Russom

Bradbury

Broderius

et al. 1997

440

401

“…The classification of a compound as a reactive toxicant also is complicated by the potential role of metabolic activation. Research addressing principles underlying the means of estimating routes and rates of metabolic activation from chemical structure provides a range of potential approaches to improve this aspect of predicting modes of toxic action [85–88].…”

Section: Qsar Developmentmentioning

confidence: 99%

Overview of data and conceptual approaches for derivation of quantitative structure-activity relationships for ecotoxicological effects of organic chemicals

Bradbury

Russom

Ankley

et al. 2003

Abstract-The use of quantitative structure-activity relationships (QSARs) in assessing potential toxic effects of organic chemicals on aquatic organisms continues to evolve as computational efficiency and toxicological understanding advance. With the everincreasing production of new chemicals, and the need to optimize resources to assess thousands of existing chemicals in commerce, regulatory agencies have turned to QSARs as essential tools to help prioritize tiered risk assessments when empirical data are not available to evaluate toxicological effects. Progress in designing scientifically credible QSARs is intimately associated with the development of empirically derived databases of well-defined and quantified toxicity endpoints, which are based on a strategic evaluation of diverse sets of chemical structures, modes of toxic action, and species. This review provides a brief overview of four databases created for the purpose of developing QSARs for estimating toxicity of chemicals to aquatic organisms. The evolution of QSARs based initially on general chemical classification schemes, to models founded on modes of toxic action that range from nonspecific partitioning into hydrophobic cellular membranes to receptor-mediated mechanisms is summarized. Finally, an overview of expert systems that integrate chemical-specific mode of action classification and associated QSAR selection for estimating potential toxicological effects of organic chemicals is presented.

A QSAR for steroidal compound interaction with cytochrome P4501A1

Chan

Hoixebone

1995

The well‐known binding and metabolism of polycyclic aromatic hydrocarbons (PAHs) by cytochrome P4501A1 has led to a proposed metabolic specialization of P4501A1 to endogenous hormones. To assess this hypothesis, the binding affinities of nine steroidal molecules of increasing multiple bond content and the aromatic compound chrysene were tested against a standard ethoxyresorufin O‐deethylation assay. Both the hydrophobicity and the planarity of these molecules correlate to their binding efficiency. However, the product of these two properties shows a much stronger correlation than each separately. By using standard mathematical identities, hydrophobicity and planarity can be related to the enthalpy and entropy of activation, respectively. In this model, the hydrophobicity represents the adhesiveness per unit contact area with the active site, and the planarity the proportion of molecular structures in contact with the site. The net adhesiveness is therefore accidentally largest for the xenobiotic PAH structures.