Acute Toxicity: Fumarate is also an endogenous electrophile and reacts spontaneously with cysteine residues in proteins by a Michael addition reaction to form S-(2-succinyl) cysteine, a process termed succination. Lachrymators such as fumarate are thought to act by attacking sulfhydryl functional groups in enzymes. One of the most probable protein targets is the TRPA1 ion channel that is expressed in sensory nerves (trigeminal nerve) of the eyes, nose, mouth and lungs.

Chronic Toxicity: Fumarate is increasingly being identified as an oncometabolite. Fumarase or fumarate hydratase (FH) is a tumor suppressor, whose mutation is associated with the development of leiomyomata, renal cysts, and tumors. Loss of FH enzymatic activity results in accumulation of intracellular fumarate which has been proposed to act as a competitive inhibitor of 2-oxoglutarate-dependent oxygenases including the hypoxia-inducible factor (HIF) hydroxylases, thus activating oncogenic HIF pathways. Mitochondrial dysfunction is also associated with FH deficiency. Fumarate hydratase-deficient cells and tumors have been shown to accumulate fumarate to very high levels with multiple consequences including the activation of oncogenic pathways (A15199). Fumarate (and succinate) inhibit the activity or function of other members of the 2-oxoglutarate-dependent oxygenase superfamily, including histone demethylase enzymes (HDMs) and the TET family of 5-methlycytosine (5mC) hydroxylases which are critical in epigenetic regulation of gene expression.. Fumarate accumulation may also affect cytosolic pathways by inhibiting the reactions involved in the biosynthesis of arginine and purine.  More recently it has been found that fumarate promotes p65 phosphorylation and p65 accumulation at the HIF-1α promoter through non-canonical signaling via the upstream Tank Binding Kinase 1 (TBK1). Fumarate is also an endogenous electrophile and reacts spontaneously with cysteine residues in proteins by a Michael addition reaction to form S-(2-succinyl) cysteine, a process termed succination. Accumulation of cellular fumarate has been shown to correlate directly with an increase in succinated proteins. Targets for succination include the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, adiponectin, cytoskeletal proteins, and endoplasmic reticulum chaperone proteins. Furthermore, evidence suggests that succination of these proteins in cells may impair their functions.