| Autor: |
Ray SD; College of Pharmacy, University of New Mexico, Albuquerque 87131., Sorge CL, Raucy JL, Corcoran GB |
| Jazyk: |
angličtina |
| Zdroj: |
Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 1990 Nov; Vol. 106 (2), pp. 346-51. |
| DOI: |
10.1016/0041-008x(90)90254-r |
| Abstrakt: |
Hepatotoxic doses of acetaminophen cause early impairment of Ca2+ homeostasis in the liver. This in vivo study considers the nucleus as a possible site of lethal Ca2+ action by evaluating whether acetaminophen raises Ca2+ in this compartment, whether DNA becomes altered, and whether DNA changes occur early enough during injury to contribute causally to necrosis. Fed Swiss mice were treated with 600 mg/kg acetaminophen ip and livers and blood samples were collected over time. Total nuclear Ca2+ accumulation and fragmentation damage to DNA showed modest parallel increases between 2 and 6 hr, followed by greater than 200% rises at 12 hr mirroring the appearance of frank liver injury (ALT greater than 10,000 U/liter). However, agarose gel electrophoresis revealed extensive loss of large genomic DNA from 2 hr onward, accompanied by the appearance of periodic DNA fragments. Thus, acetaminophen raised nuclear Ca2+ concentrations and promoted DNA fragmentation in vivo. The considerable cleavage of DNA seen at late times probably resulted from cell death, whereas loss of large genomic DNA from 2 hr onward appeared at an early enough point in time to be a contributing factor in acetaminophen-induced liver necrosis. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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