The covalent binding of 1,1,2,2-tetrachloroethane to macromolecules of rat and mouse organs
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A Colacci1, S Grilli, G Lattanzi
1Centro Interuniversitario per la Ricerca sul Cancro, Università degli Studi di Bologna, Italy.
Abstract:
The in vivo interaction of the hepatocarcinogen 1,1,2,2-tetrachloroethane (1,1,2,2-TTCE) with DNA, RNA, and proteins of male Wistar rats and BALB/c mice was measured 22 hr after i.p. injection. Covalent binding index (CBI) to liver DNA was about 500 and was comparable to those of carcinogens classified as moderate initiators. It was higher than those of other chloroethanes, even than that of 1,2-dichloroethane (1,2-DCE), a symmetrically substituted haloethane whose genotoxicity has been widely demonstrated. In in vitro cell-free systems, 1,1,2,2-tetrachloroethane was bioactivated by mixed-function oxidase(s) and glutathione-S-transferase(s) (GSH-T) from microsomal and cytosolic fractions of rat and mouse liver and, to a lesser extent, of mouse lung. The in vitro activation led to formation of reactive species capable of binding to exogenous DNA and to the subcellular constituents of enzymatic fractions. These data, along with previous literature reports, provide sufficient evidence of 1,1,2,2-TTCE genotoxicity.
Insights
The hepatocarcinogen 1,1,2,2-tetrachloroethane (1,1,2,2-TTCE) shows significant genotoxicity in vivo and in vitro. Its covalent binding index to DNA is comparable to moderate carcinogens, indicating potential health risks.
Area of Science:
- Toxicology
- Molecular Biology
- Carcinogenesis
Background:
- Hepatocarcinogen 1,1,2,2-tetrachloroethane (1,1,2,2-TTCE) is a suspected liver carcinogen.
- Understanding its interaction with biological macromolecules is crucial for risk assessment.
Purpose of the Study:
- To investigate the in vivo and in vitro genotoxicity of 1,1,2,2-TTCE.
- To determine the bioactivation pathways and reactive species formation.
Main Methods:
- In vivo covalent binding assay in male Wistar rats and BALB/c mice.
- In vitro bioactivation studies using liver and lung enzymatic fractions (mixed-function oxidases and glutathione-S-transferases).
- Measurement of binding to exogenous DNA and subcellular constituents.
Main Results:
- Significant in vivo covalent binding of 1,1,2,2-TTCE to liver DNA, RNA, and proteins.
- Covalent binding index (CBI) to liver DNA was approximately 500, comparable to moderate carcinogen initiators.
- 1,1,2,2-TTCE was bioactivated in vitro by MFOs and GSH-T to reactive species that bind to DNA and cellular components.
Conclusions:
- 1,1,2,2-TTCE exhibits significant genotoxicity both in vivo and in vitro.
- The bioactivation pathways involve MFOs and GSH-T, leading to DNA-reactive species.
- These findings provide strong evidence for the genotoxicity of 1,1,2,2-TTCE.