Chapter category: Channels and Transporters
Drug-induced cholestatic liver disease
Molecular Pathogenesis of Cholestasis
Edited by: Michael Trauner and Peter JansenISBN: 0-306-48240-1
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Drug induced cholestatic liver disease is a subtype of liver injury that is characterized by predominant elevations of alkaline phosphatase and bilirubin secondary to the administration of a hepatotoxic agent. It can manifest itself as a cholestatic hepatitis or as bland cholestasis, depending upon the causative agent and the mechanism of injury. Drugs that typically cause cholestasis with hepatitis include psychotropic agents, antibiotics and nonsteroidal antiinflammatory drugs (NSAIDs). The mechanism is immunoallergic and results from hypersensitivity. Pure cholestasis without hepatitis is observed most frequently with contraceptive and 17a-alkylated androgenic steroids and the mechanism most likely involves interference with hepatocyte canalicular efflux systems for bile salts, organic anions and phospholipids. The rate-limiting step in bile formation is considered to be the bile salt export pump (BSEP) mediated translocation of bile salts across the canalicular hepatocyte membrane. Inhibition of BSEP function by metabolites of cyclosporine A, troglitazone, bosentan, rifampicin and sex steroids is an important cause of drug induced cholestasis. Appropriate screening systems for inhibition of BSEP by drug metabolites have been established in membrane vesicles from Sf9 insect cells overexpressing the BSEP protein. A newly recognized mechanism of drug interactions that could cause cholestasis involves the activation of nuclear receptor signaling cascades which affect the transcription of hepatocyte transporter genes critical for bile formation. The multiple factors that regulate transcription of, for example, the BSEP, multidrug resistance protein 2 (MRP2) and multidrug resistance gene product 3 (MDR3) genes are likely targets for untoward effects of xenobiotics on hepatocyte transport function and disposal of toxic metabolites from the liver.
Additional chapters from this book:
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