Structural and functional integrity of rat liver perfused in backward and forward directions

Schölmerich, Jürgen; Kitamura, Shigehiro; Miyai, Katsumi

doi:10.1007/bf01852192

Cited by 6 publications

(1 citation statement)

References 28 publications

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“…The baseline values for bile flow (1.04 + 0.08 ~tl/g per min), bile salt secretion (6.3 ___ 0.08nmol/g per min), and bile acid hydroxylation pattern were in the range of those reported in the literature [12,13,22,23]. TLC when infused without other bile salts was taken up during the 30 min of perfusion at a rate of 93%-96%.…”

Section: Resultssupporting

confidence: 58%

Taurohyocholate, taurocholate, and tauroursodeoxycholate but not tauroursocholate and taurodehydrocholate counteract effects of taurolithocholate in rat liver

et al. 1990

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The infusion of taurolithocholate (TLC) in vivo or in the isolated perfused liver of the rat causes cholestasis and cellular necrosis. In order to analyze the protective effect of bile salts differing in number and steric position of their hydroxy groups against TLC-induced cholestasis, isolated rat livers were perfused with taurocholate (TC), taurohyocholate (THC), tauroursocholate (TUC), taurodehydrocholate (TDHC), and tauroursodeoxycholate (TUDC) (16 and 32 ~tmol/1) with or without TLC (8 and 16 ~tmol/1). Bile flow, bile salt secretion, and the hydroxylation pattern of the bile salts secreted were analyzed.TLC caused complete cholestasis after 15 min of perfusion. All bile salts studied had a protective effect. THC, TC, and TUDC completely abolished the cholestasis induced by TLC while TUC did so only for the first 10 min. TDHC was protective only as long as it was biotransformed into hydroxyoxo bile salts.Coinfusion of bile salts did not influence uptake of TLC (_> 93% of dose). Differences were found regarding the amount of TLC biotransformed (% of uptake): TC 50%; THC 32%; TUDC 36%, TUC 20%. Light microscopy revealed cellular necrosis, and dilated canaliculi were found in livers perfused with TLC only or in combination with TUC or TDHC, while the other bile salts prevented these changes.We conclude that bile salts with low micelle-forming capacity have little protective effect against TLC-induced cholestasis. These bile salts induce less biotransformation of TLC than TC, THC, and TUDC. The protective effect is not dependent on the hydrocholeretic effect of the added bile salt and is not due to an uptake inhibition.

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Section: Resultssupporting

confidence: 58%

Taurohyocholate, taurocholate, and tauroursodeoxycholate but not tauroursocholate and taurodehydrocholate counteract effects of taurolithocholate in rat liver

et al. 1990

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The multiple-indicator dilution technique for characterization of normal and retrograde flow in once-through rat liver perfusions

et al. 1989

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The technique of normal and retrograde rat liver perfusion has been widely used to probe zonal differences in drug-metabolizing activities. The validity of this approach mandates the same tissue spaces being accessed by substrates during both normal and retrograde perfusions. Using the multiple-indicator dilution technique, we presently examine the extent to which retrograde perfusion alters the spaces accessible to noneliminated references. A bolus dose of 51Cr-labeled red blood cells, 125I-albumin, 14C-sucrose and 3H2O was injected into the portal (normal) or hepatic (retrograde) vein of rat livers perfused at 10 ml per min per liver. The outflow perfusate was serially collected over 220 sec to characterize the transit times and the distribution spaces of the labels. During retrograde perfusion, red blood cells, albumin and sucrose profiles peaked later and lower than during normal perfusion, whereas the water curves were similar. The transit times of red blood cells, albumin and sucrose were longer (p less than 0.005), whereas those for water did not change. Consequently, retrograde flow resulted in significantly larger sinusoidal blood volumes (45%), albumin Disse space (42%) and sucrose Disse space (25%) than during normal flow, whereas the distribution spaces for total and intracellular water remained unaltered. The distension of the vascular tree was confirmed by electron microscopy, by which occasional isolated foci of widened intercellular recesses and spaces of Disse were observed. Cellular ultrastructure was otherwise unchanged, and there was no difference found between normal and retrograde perfusion for bile flow rates, AST release, perfusion pressure, oxygen consumption and metabolic removal of ethanol, a substrate with flow-limited distribution, which equilibrates rapidly with cell water (hepatic extraction ratios were virtually identical: normal vs. retrograde, 0.50 vs. 0.48 at 6 to 7.4 mM input concentration). These findings suggest that the functional and metabolic capacities of the liver remain unperturbed during retrograde perfusion, rendering the technique suitable for the investigation of zonal differences in drug-metabolizing enzymes.

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Competing pathways in drug metabolism. II. An identical, anterior enzymic distribution for 2- and 5-sulfoconjugation and a posterior localization for 5-glucuronidation of gentisamide in the rat liver

Morris

Yuen

Pang

1988

Journal of Pharmacokinetics and Biopharmaceutics

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Gentisamide (2,5-dihydroxybenzamide, GAM), a substrate that forms two monosulfates at the 2 and 5 positions (GAM-2S and GAM-5S) and a monoglucuronide at the 5 position (GAM-5G), was delivered at 8 or 80 microM by normal (N) and retrograde (R) flows to the once-through rat liver preparation. At the lower (8 microM) input concentration, ratios of conjugate formation rate, GAM-5S/GAM-5G and GAM-2S/GAM-5G, were decreased significantly (4.01 +/- 1.42 to 2.93 +/- 0.99, and 1.13 +/- 0.65 to 0.66 +/- 0.41, respectively) whereas a small but significant increase in the steady-state extraction ratio, E (0.89 +/- 0.029 to 0.94 +/- 0.016), was observed upon changing the flow direction from N to R. At the higher input GAM concentration (80 microM), conjugate formation rate ratios were relatively constant for GAM-5S/GAM-5G (1.18 +/- 0.08 to 1.11 +/- 0.12) and GAM-2S/GAM-5G (0.33 +/- 0.05 to 0.31 +/- 0.05) upon changing flow direction from N to R, despite a slight increase in E from 0.87 +/- 0.023 to 0.91 +/- 0.016 was observed. These results suggest that the sulfotransferase activities responsible for 2- and 5-sulfoconjugations are identically distributed and localized anterior to 5-glucuronidation activities during a normal flow of substrate into the rat liver (entering the portal vein and exiting the hepatic vein), and that the presence of uneven distribution of conjugation activities is discriminated only at the lower input drug concentration. At high concentration (greater than Km for all systems), saturation of all pathways occurs, and other anteriorly/identically distributed competing pathways would fail to perturb downstream intrahepatic drug concentrations and the resultant conjugation rates. The lack of change in metabolic profiles renders the condition unsuitable for examination of uneven distribution of enzymes in the liver. These observations were generally predicted by theoretical enzymic models of consistent distribution patterns. Because 2- and 5-sulfation were mediated by systems of similar Km but different Vmax values, two possibilities, the same isozyme of sulfotransferase being involved in the formation of two enzyme-substrate complexes to form two distinctly different products or two isozymes of sulfotransferases of identical distribution, were discussed.

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Structural and functional integrity of rat liver perfused in backward and forward directions

Cited by 6 publications

References 28 publications

Taurohyocholate, taurocholate, and tauroursodeoxycholate but not tauroursocholate and taurodehydrocholate counteract effects of taurolithocholate in rat liver

Taurohyocholate, taurocholate, and tauroursodeoxycholate but not tauroursocholate and taurodehydrocholate counteract effects of taurolithocholate in rat liver

The multiple-indicator dilution technique for characterization of normal and retrograde flow in once-through rat liver perfusions

Competing pathways in drug metabolism. II. An identical, anterior enzymic distribution for 2- and 5-sulfoconjugation and a posterior localization for 5-glucuronidation of gentisamide in the rat liver

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