Elucidating mechanism of drug induced toxicity

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Kupffer cells release reactive oxygen species (ROS), cytokines, and chemokines, which induce neutrophil extravasation and activation.

The liver expresses many cytochrome P450 isoforms, including ethanol-induced CYP2E1.

About 75% of hepatic blood comes directly from the gastrointestinal viscera and spleen via the portal vein.

Portal blood brings drugs and xenobiotics absorbed by the gut directly to the liver in concentrated form.

The intrinsic hepatotoxicity of these hydrophobic, sterol-derived molecules is apparent in children who have a mutation in the bile salt excretory pump in the canalicular membrane (Strautnieks ., 1998).

elucidating mechanism of drug induced toxicity-62

Hepatocytes are highly reliant on ATP for ureagenesis, gluconeogenesis, and fatty acid metabolism among many other metabolic processes.The sections that follow emphasize important injury mechanisms, which can be a consequence of metabolism and/or direct cell toxicity of chemicals.These mechanisms include bile acid-induced liver cell injury during cholestasis, pathophysiological effects of mitochondrial dysfunction, and cell damage by reactive oxygen and nitrogen species.CYP2E1 generates ROS, activates many toxicologically important substrates, and may be the central pathway by which ethanol causes oxidative stress.In acetaminophen toxicity, nitric oxide (NO) scavenges superoxide to produce peroxynitrite, which then causes protein nitration and tissue injury.

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