Isolated Rat Liver Preparation. Bile Production and Other Basic Properties.

Bräuer, Ralph W.; Pessotti, Rita L.; Pizzolato, P.

doi:10.3181/00379727-78-19012

Cited by 111 publications

(28 citation statements)

References 2 publications

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“…Livers from male Wistar rats (Iffa Credo, Lyon, France) were isolated and perfused with recirculation of the perfusion medium according to the design originally described by Brauer et al (1951) and modified by Sabouraud et al (1993). The recirculating perfusate (approximately 180 ml), oxygenated with oxygencarbon dioxide (95%:5%), was a Krebs-Ringer bicarbonate buffer supplemented with glucose (1.3 mM) and bovine serum albumin (0.5%).…”

Section: Materials and Methods Iprl Experimentsmentioning

confidence: 99%

5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model

Arellano

Mc²,

Martino³

et al. 1997

Br J Cancer

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Summary We studied the effects of 5-ethynyluracil (GW776), a potent inactivator of dihydropyrimidine dehydrogenase, on the metabolism of 5-fluorouracil (5-FU), in particular with respect to formation of the toxic compounds fluoroacetate (FAC) and 2-fluoro-3-hydroxypropionic acid (FHPA), using fluorine-19 nuclear magnetic resonance and the isolated perfused rat liver model. Livers were perfused with 5-FU alone at a dose of 15 mg kg-' body weight or with 5-FU + GW776 at doses of 15 mg 5-FU kg-' body weight and 0.5 mg GW776 kg-' body weight injected 1 h before 5-FU. All 5-FU was metabolized in experiments with 5-FU alone whereas unmetabolized 5-FU represented 94% of the fluorinated compounds measured in experiments with 5-FU + GW776. GW776 modulated both the catabolic and the anabolic pathways of 5-FU, the most striking effect being on the degradative pathway. The amount of 5-FU catabolites decreased by a factor of 27 in the presence of GW776. The modulator led to a decrease in a-fluoro-3-alanine (FBAL) formation by a factor of approximately 110, while fluoride ion formation decreased by a factor of approximately 10. By strongly lowering the metabolism of 5-FU into FBAL, GW776 circumvented the transformation of FBAL into toxic FAC and FHPA. 5-FU anabolites increased by a factor of approximately 7 in the presence of GW776. The level of free fluoronucleotides and 5-fluorouridine-5'-diphosphate sugars was increased up to fivefold. No incorporation of 5-FU into RNA could be measured in experiments with 5-FU alone whereas, although low (0.1% of 5-FU injected dose), it was detectable in experiments with 5-FU + GW776. These results suggest that GW776 may be useful for attenuating the not very common but serious cardiotoxic and/or neurotoxic side-effects of 5-FU that are probably due to FBAL metabolites.Keywords: 5-fluorouracil; 5-ethynyluracil (GW776); 19F nuclear magnetic resonance; modulation of 5-fluorouracil metabolism; fluoroacetate; 2-fluoro-3-hydroxypropionic acid; isolated perfused rat liver 5-Fluorouracil (5-FU) is one of the most commonly used anticancer agents for treatment of solid tumours. Common clinical adverse reactions include myelosuppression, diarrhoea, vomiting and mucositis. Over the last decade, the number of reports of cardiotoxicity and neurotoxicity attributed to 5-FU has rapidly increased (Anand, 1994;Yeh and Cheng, 1994; and references cited therein). The biochemical mechanism underlying these toxic side-effects remains unclear, although it has been postulated that 5-FU, and more precisely its main catabolite ex-fluoro-p-alanine (FBAL) (Mukherjee and Heidelberger, 1960;Bemadou et al, 1985; Heggie et al, 1987; Hull et al, 1988), might be transformed into fluoroacetate (FAC) (Koenig and Patel, 1970), a highly cardiotoxic and neurotoxic poison (Pattison and Peters, 1966). We demonstrated on the isolated perfused rabbit heart model that commercial solutions of 5-FU contain cardiotoxic impurities, namely fluoromalonic acid semialdehyde (FMASAld) and fluoroacetaldehyde (Facet), that are derived from...

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Section: Materials and Methods Iprl Experimentsmentioning

confidence: 99%

5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model

Arellano

Mc²,

Martino³

et al. 1997

Br J Cancer

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“…The apparatus and general perfusion procedures were based on the method developed by Brauer, Pessotti, and Pizzolato (20) for isolated rat liver and are the same as described by us using isolated hamster liver (19 The liver was freed from its attachment and transferred to the perfusion apparatus where it was placed with its diaphragmatic surface on a sheet of siliconized rubber in an evaporating dish. The dish contained a 5 mm aperture in the bottom through which the outflow cannula in the inferior vena cava protruded.…”

Section: Methodsmentioning

confidence: 99%

Cholestasis induced by sodium taurolithocholate in isolated hamster liver

King¹,

Schoenfield²

1971

J. Clin. Invest.

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“…This was done to study the added effect of carbon tetrachloride injury on the plasma pigments inasmuch as the exposure alone did not produce jaundiced plasma. Rat liver perfusion preparations (15) were utilized in the study of pigments in bile produced by the isolated liver in response to acute CC14 injury.…”

Section: Methodsmentioning

confidence: 99%

Sulfate and Glucuronide Conjugates of Bilirubin in Experimental Liver Injury*

Schoenfield¹,

Bollman²,

Hoffman³

1962

J. Clin. Invest.

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Free, water-insoluble, indirect-reacting bilirubin is conjugated prior to excretion, predominantly as an ester monoglucuronide and a diglucuronide, forming the water-soluble, direct-reacting pigments I and II, respectively (1-6). The conjugation of bilirubin with glucuronic acid, in the presence of uridine diphosphate glucuronic acid which serves as a glucuronyl donor, is brought about by the enzyme, glucuronyl transferase. It has been shown that conjugated bilirubin also contains nonglucuronide conjugates (7-13).Isselbacher and McCarthy (12), using S35-labeled sulfate, identified bilirubin sulfate chromatographically and radioautographically in the bile of rats, cats, and humans and in the serum and urine of rats with ligated bile ducts. They observed that the enzymatic biosynthesis of bilirubin sulfate in vitro involves active sulfate and requires adenosine triphosphate. These same authors speculated that the proportions of glucuronide and sulfate conjugates might be altered in certain disease states.The present study was designed to investigate the relative proportions of glucuronide and sulfate conjugates of bilirubin of laboratory animals after hepatic injury. We also examined the relative proportions of pigments I and II under these same conditions (14). MATERIALS AND METHODSExperimental conditions. Male Wistar rats, weighing 250 to 300 g, were used. Each experimental group contained 6 animals except those groups used for study of bile from the isolated liver, each of which contained 4 animals. To accomplish acute injury, animals were exposed in a closed chamber to vapors of carbon tetrachloride of constant concentration (25 mg CC1, per 50 L air) for 7 hours. Bile fistulas were prepared by cannulating the common bile ducts with polyethylene catheters. The common bile duct was ligated securely with two ties of * Abridgment of thesis submitted by Dr. Schoenfield to the Faculty of the Graduate School of the University of Minnesota in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medicine.4-0 braided silk and the duct was cut between the ties for studies of short (acute) obstruction (24 hours) and of prolonged obstruction (6 to 10 days). In one group acute obstruction was accomplished after exposure to CCl4. This was done to study the added effect of carbon tetrachloride injury on the plasma pigments inasmuch as the exposure alone did not produce jaundiced plasma. Rat liver perfusion preparations (15) were utilized in the study of pigments in bile produced by the isolated liver in response to acute CC14 injury.After bile fistulas were prepared in the control groups and in the other groups in which CC14 was given later, 100 tec inorganic radioactive sulfate (S3O,) in normal saline solution was injected intraperitoneally or into the isolated liver system. Bile was then collected for 5 hours on ice and in the dark. For study of the plasma pigments the radioactive-labeled sulfate was administered immediately after obstruction in the acute experiments and 24 hours prior to the ti...

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Isolated Rat Liver Preparation. Bile Production and Other Basic Properties.

Cited by 111 publications

References 2 publications

5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model

5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model

Cholestasis induced by sodium taurolithocholate in isolated hamster liver

Sulfate and Glucuronide Conjugates of Bilirubin in Experimental Liver Injury*

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