Development of a Theoretical Model to Assess the Hepatocarcinogenic Potential of Chemicals Using Structure-Activity Relationships and the Rat Hepatocyte Assay
Abstract
The six isomeric dinitrotoluenes (DNT), of which one is known to be a heatocarcinogen (2,6-DNT), were evaluated for cytotoxic effects (inhibition of protein synthesis, lipid peroxidation, and intracellular enzyme release) in rat hepatocyte assay. Cytotoxic effects, as measured by lactate dehydrogenase (LDH) release, were correlated with the C-atomic charge of car-bon atoms bearing nitro groups for each NT isomer. Isomers with nitro groups oriented ortho or para to each other (2,3-DNT, 2,6-DNT) were more potent cytotoxic (ms) than the meta- oriented isomers (2,4-DNT, 3,4-DNT, 2,5-DNT) both in respect to LDH release and to inhibition of protein synthesis. Lipid peroxidation was not enhanced. High- performance liquid chromatographic profiles of the hepatocyte suspensions indicated that nitro group reduction was the predominant route of metabolism for all isomers except 2,6-DNA, where methyl group oxidation to produce the benyl alcohol was the major routes of transformation. Atomic charges for all atoms in the DNT molecules were calculated by the semiempirical MNDO molecular orbital method. A linear correlation was developed when the log EC sub 20 concentration for LDH release was plotted against C-atomic charge for reactive nitro groups. This correlation was used to predict the EC sub 20 values for untested nitroaromatic compounds.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 1985
- Accession Number
- ADA174459
Entities
People
- Carol E. Green
- Charles A. Tyson
- Charles L. Myers
- Ronald J. Spanggord
- Susanna E. Levalley
Organizations
- SRI International