Relationship: 271
Title
Upstream event
Alkylation, ProteinDownstream event
Peptide Oxidation
Key Event Relationship Overview
AOPs Referencing Relationship
Taxonomic Applicability
Sex Applicability
Life Stage Applicability
How Does This Key Event Relationship Work
Alkylating agents are highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. Covalent protein alkylation by reactive electrophiles was identified as a key triggering event in chemical toxicity. Protein alkylation disturbs the cellular redox balance through interaction with gluthathione, which leads to disruption of multiple biochemical pathways in exposed cells and is associated with mitochondrial dysfunction which in turn can trigger the death of exposed cells via either apoptosis and/or necrosis. Alkylating agents may substitute alkyl groups for hydrogen atoms on DNA, resulting in the formation of cross links within the DNA chain and thereby resulting in cytotoxic, mutagenic, and carcinogenic effects. The end result of the alkylation process results in the misreading of the DNA code and the inhibition of DNA, RNA, and protein synthesis and the triggering of programmed cell death (apoptosis).
Weight of Evidence
Quantitative Understanding of the Linkage
Evidence Supporting Taxonomic Applicability
References
Kehrer and Biswal (2000) Toxicological Sciences 57, (6-15)
Liebler DC, Chem Res Toxicol. 2008 January ; 21(1): 117–128