Increased paracellular permeability in intrahepatic cholestasis induced by carmustine (BCNU) in rats

Journal Article · Mon Jul 01 00:00:00 EDT 1991 · Gastroenterology; (United States)

OSTI ID:5595226

Krell, H; Fromm, H; Larson, R E ^[1]

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1. Pharmakologisches Institut, Universitaet Tuebingen (Germany)

Carmustine (i.e., 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)) is a drug with cholestatic potency both in experimental animals and in humans. To study the mechanisms involved in the development of the hepatic lesions, early changes in liver function in rats pretreated with the drug were investigated. Dosages and sampling times that did not result in hepatocellular injury, as indicated by release of marker enzymes, were applied. In isolated perfused livers from pretreated rats, bile flow and maximal secretion rate of taurocholate were decreased. An increase in biliary {sup 14}Csucrose clearance suggested enhanced permeability of the bile tract and was correlated with increased inorganic phosphate concentration in bile. To assess the contribution of paracellular and transcellular pathways of sucrose, {sup 14}Csucrose access into bile was analyzed by biliary off-kinetics after omission of the radioactive marker from the perfusion medium. An improved method was developed to quantitate the permeability of the bile tract by applying the classical flow equation to the paracellular portion of biliary sucrose clearance. With this method it was shown that pretreatment of rats with BCNU resulted in an increase in both diffusion and convection of paracellular sucrose from perfusate into bile. Accordingly, the fast access of horseradish peroxidase from perfusate into bile was facilitated in isolated perfused livers of BCNU-treated rats. The results indicate that an increase in paracellular permeability is an early alteration that may contribute to the development of hepatotoxic lesions caused by BCNU. It is shown that inert solute clearance can be used to assess paracellular permeability if the paracellular fraction is determined.

• OSTI ID: 5595226
• Journal Information: Gastroenterology; (United States), Journal Name: Gastroenterology; (United States) Vol. 101:1; ISSN GASTA; ISSN 0016-5085
• Country of Publication: United States
• Language: English

Related Subjects

550501* -- Metabolism-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMALS
BILE
BILIARY TRACT
BIOLOGICAL MARKERS
BIOLOGICAL MATERIALS
BODY
BODY FLUIDS
CARBOHYDRATES
CARBON 14 COMPOUNDS
CARBON COMPOUNDS
CELL CONSTITUENTS
CELL MEMBRANES
DIGESTIVE SYSTEM
DISACCHARIDES
DRUGS
GLANDS
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
LIVER
MAMMALS
MATERIALS
MEMBRANES
METABOLISM
OLIGOSACCHARIDES
ORGANIC COMPOUNDS
ORGANS
OXYGEN COMPOUNDS
PATHOLOGICAL CHANGES
PERMEABILITY
PHOSPHATES
PHOSPHORUS COMPOUNDS
RATS
RODENTS
SACCHARIDES
SACCHAROSE
TRACER TECHNIQUES
VERTEBRATES