Acetaminophen toxicity in cultured trout liver cells. I. Morphological alterations and effects on cytochrome P450 1A1.
To better characterize the hepatotoxicity of acetaminophen, the effects of this drug were investigated on isolated liver cells from a species relatively resistant to acetaminophen toxicity, rainbow trout. At high concentrations of acetaminophen (2-10 mM), pathologic effects were detected, including loss of lactate dehydrogenase from cells, disruption of cell-cell aggregation, cell death, and distinctive alterations in cell morphology, as demonstrated by light and electron microscopic examination. Most striking was the acetaminophen-induced rearrangement of mitochondria, which were clustered adjacent to the nucleus and rarely seen at cell periphery. The endoplasmic reticulum was also altered by acetaminophen treatment. In the middle portion of the cytoplasm, parallel arrays of endoplasmic reticulum cisternae were abundant; however, the peripheral cytoplasm was restricted to vesicular profiles of endoplasmic reticulum. Although nuclei in acetaminophen-treated cells displayed peripheral heterochromatin aggregation, acetaminophen did not produce detectable DNA fragmentation, in contrast to effects reported for mouse liver cells. Thus DNA fragmentation does not appear to be required for acetaminophen to manifest cytotoxic effects. In addition, immunohistochemical studies indicated that toxic concentrations of acetaminophen which altered the endoplasmic reticulum helped maintain cytochrome P450 1A1 in liver cells from beta-naphthoflavone-induced trout.
Department of Biochemistry, West Virginia University Health Sciences Center, Morgantown 26506-9142.
M R
MR
Miller
E
E
Wentz
J B
JB
Blair
D
D
Pack
D E
DE
Hinton
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002449:Cell Aggregation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D004247:DNA / Q000378:metabolism / Q000648:ultrastructure; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000648:ultrastructure; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism / Q000502:physiology; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D008853:Microscopy / Q000379:methods; D008854:Microscopy, Electron; D008928:Mitochondria / Q000648:ultrastructure; D010088:Oxidoreductases / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D014337:Trout / Q000502:physiology*
D002843:Chromatin; D000082:Acetaminophen; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D007770:L-Lactate Dehydrogenase; D019363:Cytochrome P-450 CYP1A1