From experimental models, several mechanisms have been postulated for impaired bile secretion. They are inhibition of Na+, K+ ATPase resulting in reduced uptake of bile acids, increased pericel-lular permeability and regurgitation into plasma of bile constituents, impaired intracellular transport due to cytoskeletal dysfunction, altered intracel-lular calcium homeostasis or altered canalicular carriers (Erlinger, 1997). A recent study demonstrated that oestrogen metabolites trans-inhibit the bile salt export pump in rat liver providing a molecular basis for drug-induced cholestasis (Stieger et al, 2000).
Microvesicular steatosis occurs in conditions characterised by severe impairment of the mito-chondrial ^-oxidation process. Drugs can sequester coenzyme A (aspirin, valproic acid), inhibit mitochondrial ^-oxidation enzymes (tetracycline), and, in addition, inhibit oxidative phosphorylation (amiodarone, perhexiline). When ^-oxidation is severely impaired, fatty acids, which are poorly oxidized by mitochondria, are mainly esterified into triglycerides and accumulate as small vesicles (Fromenty et al., 1997).
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