Drug-induced intrahepatic cholestasis: characterization of different pathomechanisms

Abstract

The pathogenesis of intrahepatic cholestasis in rats was studied using isolated perfused livers as an experimental model. Three basic mechanisms were differentiated: 1. Permeabilization of the bilio-sinusoidal barrier associated with electron microscopic alterations of the tight junctional complexes was found in livers of rats treated with α-naphthylisothiocyanate (ANIT, 250 mg/kg body weight). Consequences of these alterations were: reflux of bile constituents such as taurocholate and sulfobromophthalein and increased access to the biliary space of paracellular markers such as inulin and sucrose. The clear-cut mechanism of ANIT cholestasis was used to distinguish other mechanisms of intrahepatic cholestasis. 2. Inhibition of the basic process of fluid secretion was found to be the primary event in the development of cholestasis induced by estrogens. After 5 days of treating rats with ethinyl estradiol (5 mg/kg/day), bile flow was diminished in isolated livers while the permeability of the biliary tract to sucrose and inulin was not affected. Accordingly, the maximal concentration of taurocholate in bile was increased, indicating that its secretion was sustained. The same effect was observed after 1 week of treatment with the depot estrogen estradiol valerate (1 mg/kg/week). After 3 weeks of treatment, however, the taurocholate concentration in bile was lowered and the clearance of sucrose was increased. Bile flow remained at the same cholestatic level for 20 weeks. These results suggest that estrogens have the potency to increase tight junctional permeability only in a second step in the development of cholestasis, following the inhibition of bile flow. 3. An additional mode of secretory inhibition was induced by lowering the concentration of Ca²⁺ in the perfusate of isolated liver. Using ANIT-pretreated livers, i. e., livers with very low capacity to secrete foreign dyes, a high rate of efflux of sulfobromophthalein into the perfusate of preloaded livers suggests stimulation of the efflux of cholephilic solutes across the sinusoidal membrane of liver cells. The results demonstrate that the term intrahepatic cholestasis comprises a number of different sites of interference with the complex process of bile secretion.