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The hepatotoxic action of allyl formate.

ABSTRACT: The hepatotoxic action of allyl formate on rat liver has been investigated. Biochemical changes can be detected in the liver cell many hours before the histological changes and it would appear that the toxin has a direct action on the liver parenchymal cell. The results suggest that allyl formate is not the toxic agent but that it is converted via allyl alcohol into acrolein. This reaction requires the presence of alcohol dehydrogenase. Histochemical studies have shown that this enzyme is localized in the periportal region of the liver lobule, and may explain why allyl formate solely produces a periportal necrosis. As glutathione and 1,4-dithiothreitol protect against the early biochemical changes produced by the poison, it is probable that acrolein alkylates proteins and nucleic acids.

SUBMITTER: Rees KR

PROVIDER: S-EPMC1271216 | biostudies-other | 1967 Sep

REPOSITORIES: biostudies-other

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Project description:Toxin-induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti-inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the d-galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells and mortality compared with vehicle-injected controls. VLX103 decreased GalN/LPS induction of tumor necrosis factor (TNF) but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS-treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7, which resulted from reduced c-Jun N-terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 hours after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol-induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL-positive cells.ConclusionVLX103 effectively decreases toxin-induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease. (Hepatology 2017;66:922-935).

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The hepatotoxic action of allyl formate.

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