Toxicity and kinetics of [3H]microcystin-LR in isolated perfused rat livers

Judith G. Pace, Nancy A. Robinson, George A. Miura, Charles F. Matson, Thomas Geisbert, John D. White

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Isolated rat livers were perfused for 60 min with either 0.3 or 0.5 μg/ml (initial volume, 119 ml) of [3H]microcystin-LR at a constant flow of 10 ml/min in a recirculating system. During the 60-min exposure, toxin caused stimulation of glycogenolysis, liver engorgement, and cessation of bile flow. Electron micrographs of liver showed dilation of bile canaliculi and the space of Disse, loss of sinusoidal lining architecture, and decreased hepatocyte intercellular contacts. Although hepatocytes did not exhibit overt necrosis, mitochondria were hydropic, occasionally encircled by whorls of rough endoplasmic reticulum, and desmosomal tonofilaments were decreased on the plasma membrane lateral surface. Isolated mitochondria displayed inhibition of state 3 respiration and a 50-60% decrease in the respiratory control index, characteristic of hydropism. Distribution of radiolabel was 1.7% to bile, 79% to perfusate, and 16% to liver. Two to four percent was recovered in perfusate that leaked from the surface of the liver. Of the radiolabel found in bile and perfusate, 78 and 100% were associated with parent toxin, respectively. The radiolabel in liver, associated with the cytosolic fraction (S-100), corresponded to parent toxin (15%) and to a more-polar component(s) (85%). The elimination halflife from perfusate was 130 ± 10 min (0.5 μg/ml) and the hepatic extraction ratio 0.07 ± 0.01. Although the calculated hepatic extraction ratio was low, there was a significant accumulation of microcystin in the liver. Many toxic effects of microcystin in the perfused liver mimicked those observed in the whole animal, suggesting that this model can be used as an alternative to whole animals for screening of potential therapeutic agents.

Original languageEnglish (US)
Pages (from-to)391-401
Number of pages11
JournalToxicology and Applied Pharmacology
Volume107
Issue number3
DOIs
StatePublished - Mar 1 1991
Externally publishedYes

Fingerprint

Liver
Toxicity
Rats
Kinetics
Mitochondria
Bile
Animals
Hepatocytes
cyanoginosin LR
Bile Canaliculi
Poisons
Cell membranes
Glycogenolysis
Linings
Intermediate Filaments
Rough Endoplasmic Reticulum
Screening
Half-Life
Dilatation
Edema

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Toxicity and kinetics of [3H]microcystin-LR in isolated perfused rat livers. / Pace, Judith G.; Robinson, Nancy A.; Miura, George A.; Matson, Charles F.; Geisbert, Thomas; White, John D.

In: Toxicology and Applied Pharmacology, Vol. 107, No. 3, 01.03.1991, p. 391-401.

Research output: Contribution to journalArticle

Pace, Judith G. ; Robinson, Nancy A. ; Miura, George A. ; Matson, Charles F. ; Geisbert, Thomas ; White, John D. / Toxicity and kinetics of [3H]microcystin-LR in isolated perfused rat livers. In: Toxicology and Applied Pharmacology. 1991 ; Vol. 107, No. 3. pp. 391-401.
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