Morphological studies on selective acinar liver damage by N-hydroxy-2-acetylaminofluorene and carbon tetrachloride

Groothuis, Geny M. M.; Meijer, Dirk K. F.; Hardonk, M. J.

doi:10.1007/bf00508347

Cited by 19 publications

(1 citation statement)

References 35 publications

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“…Allylformate is known to produce hepatocyte necrosis in the periportal area (33) resulting from the activation by alcohol dehydrogenase to acrolein, which seems responsible for the cytotoxic effects of allylformate (34). CCl,, on the other hand, produces hepatocyte necrosis in the perivenous zone (35) as a consequence of its conversion to the CC13 radical by cytochrome P-450-dependent oxidation. As obvious from the histological appearance of the liver tissue and the increase in the serum levels of some diagnostic enzymes, the doses and exposure times for both allylformate and CC1, were sufficient to cause various degrees of cell damage in the respective zones, including massive cell necrosis under the more drastic conditions.…”

Section: Discussionmentioning

confidence: 99%

Alterations of hepatic enzyme levels and of the acinar distribution of glutamine synthetase in response to experimental liver injury in the rat

et al. 1988

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Glutamine synthetase shows a striking heterogeneous distribution in normal rat liver as consistently revealed by immunohistochemistry using a specific antiserum against the rat liver enzyme or a cross-reacting antiserum. The effects of zonal liver injury induced by allylformate or CCl4 on this distribution and on the activity of glutamine synthetase as well as of enzymes with different acinar distribution were investigated. Treatment with allylformate or CCl4 at appropriate concentrations led to severe hepatocyte necrosis in the periportal and perivenous zone, respectively, as revealed by histological examination and by the levels of serum marker enzymes. Exposure to allylformate (50 to 100 microliter per kg) for less than 1 day did not change the distribution and activity of glutamine synthetase but reduced the specific activities of the urea cycle enzymes. In contrast, treatment with CCl4 (1,000 microliter per kg) strongly reduced the activity and the acinar region covered by glutamine synthetase but not, for instance, the activities of the urea cycle enzymes. These results in conjunction with the data obtained for other enzymes indicate that a short exposure to these hepatotoxins affects different enzyme activities in close accord with their preferential acinar localization. During prolonged exposure this initial response was often modified due to adaptation. In the case of glutamine synthetase, however, no adaptive appearance of glutamine synthetase in other parts of the acinus could be detected even if the cell population originally expressing this phenotype was destroyed. This extremely inflexible distribution suggests that glutamine synthetase expression is a matter of cell differentiation rather than of modulation by nutritional and hormonal factors (or their acinar gradients) as found for many other hepatic enzymes.

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Section: Discussionmentioning

confidence: 99%

Alterations of hepatic enzyme levels and of the acinar distribution of glutamine synthetase in response to experimental liver injury in the rat

et al. 1988

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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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Hypoxia and Cci4–Induced Liver Injury, But Not Acidosis, Impair Metabolism of Cysteinyl Leukotrienes in Perfused Rat Liver

Wettstein¹,

Gerok²,

Häussinger³

1990

Hepatology

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Uptake, metabolism and biliary elimination of infused cysteinyl leukotrienes were investigated in single-pass perfused rat liver. Hypoxia did not impair uptake of infused [3H]leukotriene C4, but inhibited biliary excretion of radioactivity by about 50% compared with normoxic control experiments. In addition, the leukotriene metabolite pattern in bile was profoundly altered and was characterized in hypoxia by a 75% to 80% decrease of both leukotriene C4 and polar metabolites, representing omega-oxidation products, whereas the appearance of leukotriene D4 in bile was not affected. Reoxygenation was followed by a marked increase of biliary excretion of polar metabolites, indicating that leukotrienes taken up and stored in the liver cells during the hypoxic period now underwent omega-oxidation with subsequent elimination of the omega-oxidized products. Hypoxia also inhibited the biliary excretion of radioactivity after [3H]leukotriene E4 addition because of an almost complete absence of omega-oxidation products in bile, whereas N-acetyl-leukotriene E4 excretion was not affected. Induction of liver injury by carbon tetrachloride treatment decreased single-pass uptake of [3H]leukotriene C4 by 30%, and only 36% of the radioactivity taken up by the liver was eliminated into bile within 1 hr, compared with 78% in normal livers. The pattern of biliary leukotriene metabolites, however, was not significantly different. Lowering the pH in the perfusion medium from 7.4 to 7.1 had no effect on uptake, metabolism or biliary elimination of infused [3H]leukotriene C4. The data show that hypoxia and experimental liver injury, but not acidosis, impair hepatic processing of cysteinyl leukotrienes. Thus, in leukotriene-induced shock syndromes, leukotriene elimination and inactivation may be impaired giving rise to a "vicious circle."

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Morphological studies on selective acinar liver damage by N-hydroxy-2-acetylaminofluorene and carbon tetrachloride

Cited by 19 publications

References 35 publications

Alterations of hepatic enzyme levels and of the acinar distribution of glutamine synthetase in response to experimental liver injury in the rat

Alterations of hepatic enzyme levels and of the acinar distribution of glutamine synthetase in response to experimental liver injury in the rat

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

Hypoxia and Cci4–Induced Liver Injury, But Not Acidosis, Impair Metabolism of Cysteinyl Leukotrienes in Perfused Rat Liver

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