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

  • G. M. M. Groothuis
  • D. K. F. Meijer
  • M. J. Hardonk


Heterogeneity of rat hepatocytes with respect to transport function can in principle by studied by selective acinar damage of periportal (acinar zone 1) and perivenous (acinar zone 3) cells. Meaningful conclusions from such studies can be drawn only if the acinar selectivity of the toxins employed is clearly demonstrated. Therefore, transmission and scanning electron microscopy, enzyme histochemistry and determination of the increase of the activities in serum of glutamate-pyruvate transaminase, glutamate dehydrogenase and alkaline phosphatase were performed 24 h after the administration of 90 μmol/kg N-hydroxy-2-acetylamino-fluorene (N-OH-AAF) to damage zone 1 and 2.1 mmol/kg carbon tetrachloride (CCl4) to damage zone 3.

N-OH-AAF administration resulted in strongly elevated serum enzyme activities. Histochemically, a decrease of enzyme activities in a very limited number of cells in zone 1 (5–20% of the acinus) was found. The remaining cells of zone 1 showed either increased or normal activities, and zone 3 cells appeared normal. Ultrastructurally, zone 3 cells were intact, but zone 1 cells exhibited several signs of damage: among others, induction of RER into fingerprints, numerous small vesicles, and widened bile canaliculi; some necrotic cells were present.

CCl4 administration resulted in a relatively smaller rise of serum enzyme activities than N-OH-AAF, and in a decrease of histochemically detectable enzyme activities in zone 3 (20–50% of the acinus), while zone 1 cells appeared normal. Ultrastructurally, no changes were observed in zone 1, but zone 3 cells were necrotic or revealed swollen ER occupying most of the cytoplasmic space. Scanning EM showed no damage to the sinusoidal lining after both N-OH-AAF and CCl4-pretreatment. Bile canaliculi were normal after CCl4-pretreatment. It is concluded that administration of these doses of N-OH-AAF and CCl4 results in damage that is restricted to zone 1 and zone 3 respectively and therefore, enables further studies concerning the heterogeneity of hepatocytes with respect to transport functions. This study introduces N-OH-AAF as a new tool for the selective destruction of zone 1 of the liver acinus, with a better reproducibility of the hepatic lesion and a lower general toxicity compared with previously used toxins such as allylalcohol.

Key words

Heterogeneity of rat hepatocytes Selective acinar damage Carbon tetrachloride N-Hydroxy-2-acetylaminofluorene 


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Copyright information

© Springer-Verlag 1983

Authors and Affiliations

  • G. M. M. Groothuis
    • 1
    • 2
  • D. K. F. Meijer
    • 2
  • M. J. Hardonk
    • 3
  1. 1.Department of Pharmacology and Clinical PharmacologyState University of GroningenGroningen
  2. 2.Department of Pharmacology and PharmacotherapeuticsState University of GroningenGroningen
  3. 3.Department of PathologyState University of GroningenGroningenThe Netherlands

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