Fundamentals of Toxicologic Pathology by unknow

Author:unknow
Language: eng
Format: epub
ISBN: 9780128098424
Publisher: Elsevier Ltd.
Published: 2018-03-02T16:00:00+00:00

Cytotoxic Agents and Heavy Metals

Compounds that react by 1,4 addition at the β-olefinic carbon of some cellular nucleophiles (e.g., ethyl acrylate) are cytotoxic. These compounds are typically biotransformed/detoxified by conjugation to GSH, which is the dominant nonprotein sulfhydryl-containing constituent of epithelial cells that protects them from oxidative damage. Cytotoxicity occurs because GSH is consumed in the biotransformation process for inactivating the compounds. The cell is therefore more susceptible to the oxidation products that are produced during normal metabolism. Ethyl acrylate, for example, causes forestomach damage through depletion of GSH and other sulfhydryl-bearing (cysteine) groups found in thiol-containing peptides.

Cellular damage can also occur by inhibiting oxidative metabolism. Arsenates uncouple oxidative phosphorylation in the mitochondria, possibly by substituting for inorganic phosphate and forming unstable esters. Arsenic is stored in several body sites, one of which is the wall of the GI tract. Inorganic arsenicals cause hyperemia of the GI blood vessels, which, coupled with endothelial cell damage, leads to submucosal hemorrhage. Suppression of epithelial cell proliferation accentuates the damage, and hemorrhagic enteritis develops.

Cadmium causes irritation of GI epithelial cells leading to vomiting, salivation, and diarrhea. Ingestion of ionic inorganic mercury leads to precipitation of mucosal proteins and a corrosive effect on the GI mucosa. Acute inorganic mercury intoxication causes vomiting.

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