CHOLESTATIC POTENTIALS OF ALPHA-NAPHTHYLISOTHIOCYANATE (ANIT) AND BETA-NAPHTHYLISOTHIOCYANATE (BNIT) IN THE ISOLATED-PERFUSED RAT-LIVER

Previous studies in rats have shown that a single oral dose of alpha-n aphthylisothiocyanate (ANIT), but not the regioisomer beta-naphthyliso thiocyanate (BNIT), results in intrahepatic cholestasis. The present s tudies were designed to evaluate the intrinsic cholestatic potential o f ANIT and BNIT in the isolated perfused rat liver. Livers from male S prague-Dawley rats (350-450 g) were isolated and perfused with Krebs-H enseleit buffer supplemented with 50 mu M taurocholate and ANIT or BNI T (0, 5, 15 or 50 mu M). Rates of bile flow, bile acid uptake and bile acid excretion were monitored for up to 70 min. Permeability of tight junctions also was evaluated. At concentrations of 5 mu M, neither AN IT nor BNIT altered hepatobiliary function or tight junction permeabil ity. In contrast, perfusion with 50 mu M ANIT or BNIT for 35 min resul ted in decreases in bile flow rates of 19 +/- 8 and 13 +/- 4%, respect ively. After 70 min of perfusion with ANIT or BNIT, rates of bile how were decreased by 78 +/- 5 and 71 +/- 4%, respectively. Bile acid excr etion also was decreased following perfusion with 50 mu M ANIT or BNIT . Perfusion with 50 mu M ANIT or BNIT decreased bile acid uptake by 51 +/- 13 and 46 +/- 6%, respectively, at 60 min. Bile/plasma (B/P) rati os of [H-3]sucrose were not affected by ANIT or BNIT at any time durin g perfusion, indicating that changes in bile flow and bile acid excret ion in the isolated perfused liver were not associated with increased hepatocyte tight junction permeability. These data demonstrate that th e direct portal infusion of a 50 mu M concentration of either ANIT or BNIT produced marked decreases in bile flow, indicating that these iso mers have a comparable intrinsic cholestatic potential in the isolated perfused liver.