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-naphthylisothiocyanate (ANIT), but not the regioisomer beta-naphthylisothiocyanate (BNIT), results in intrahepatic cholestasis. The present studies were designed to evaluate the intrinsic cholestatic potential of ANIT and BNIT in the isolated perfused rat liver. Livers from male Sprague-Dawley rats (300-450 g) were isolated and perfused with Krebs-Henseleit buffer supplemented with 50 microM taurocholate and ANIT or BNIT (0, 5, 15 or 50 microM). 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 microM, neither ANIT nor BNIT altered hepatobiliary function or tight junction permeability. In contrast, perfusion with 50 microM ANIT or BNIT for 35 min resulted in decreases in bile flow rates of 19 +/- 8 and 13 +/- 4%, respectively. After 70 min of perfusion with ANIT or BNIT, rates of bile flow were decreased by 78 +/- 5 and 71 +/- 4%, respectively. Bile acid excretion also was decreased following perfusion with 50 microM ANIT or BNIT. Perfusion with 50 microM ANIT or BNIT decreased bile acid uptake by 51 +/- 13 and 46 +/- 6%, respectively, at 60 min. Bile/plasma (B/P) ratios of [3H]sucrose were not affected by ANIT or BNIT at any time during perfusion, indicating that changes in bile flow and bile acid excretion in the isolated perfused liver were not associated with increased hepatocyte tight junction permeability. These data demonstrate that the direct portal infusion of a 50 microM concentration of either ANIT or BNIT produced marked decreases in bile flow, indicating that these isomers have a comparable intrinsic cholestatic potential in the isolated perfused liver.
Kossor
D C
DC
Department of Toxicology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
Handler
J A
JA
Dulik
D M
DM
Meunier
P C
PC
Leonard
T B
TB
Goldstein
R S
RS
D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced*; D007536:Isomerism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010101:Oxygen Consumption; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D001647:Bile Acids and Salts; D015058:1-Naphthylisothiocyanate; C031287:2-naphthylisothiocyanate