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Effects of hepatotoxic doses of acetaminophen and furosemide on tissue concentrations of CoASH and CoASSG in vivo.

Abstract：

:The effects of hepatotoxic doses of acetaminophen on tissue concentrations of CoA in the thiol form (CoASH) and as the corresponding mixed disulfide with GSH (CoASSG) were determined to test the hypotheses that early oxidant effects of acetaminophen are expressed principally in the mitochondrial compartment and that oxidative shifts in this redox couple could be employed as biomarkers of mitochondrially compartmentalized oxidant stresses. Administration of 400 mg of acetaminophen/kg to male ICR mice did not change CoASSG concentrations at 2, 4, or 6 h, but CoASH levels were lower than in saline-treated control animals at 2 and 4 h (77 +/- 8 vs 124 +/- 14 nmol/g of liver and 66 +/- 9 vs 142 +/- 7 nmol/g of liver, respectively). HPLC analyses of acid supernatants from livers of mice treated with acetaminophen in vivo showed a peak that coeluted with an adduct generated in vitro by reaction of CoASH with N-acetyl-p-benzoquinone imine, but extensive efforts to characterize further the putative product formed in vivo have been unsuccessful. Decreases in CoASH levels were not observed in mice given comparably hepatotoxic doses of furosemide, which diminishes the concern that the decreases in CoASH levels observed in the acetaminophen-treated mice were simply secondary to injury. Hepatic CoASSG concentrations were elevated 10-20-fold 2 h after administration of 400 or 500 mg of furosemide/kg, but were not different than in saline-treated control mice at 4 or 6 h. Increases in hepatic concentrations of GSSG were observed after 6 h in both the acetaminophen-treated and the furosemide-treated mice, suggesting that these changes may be more reflective of oxidant responses to hepatic necrosis than of thiol oxidation mechanisms involved in mediating the injury. The results presented here are not consistent with oxidant stress mechanisms in initiation of hepatic necrosis by acetaminophen in vivo, but the data suggest possible roles for mitochondrially compartmentalized oxidant effects of furosemide.

journal_name

Chem Res Toxicol

journal_title

Chemical research in toxicology

authors

Rogers LK,Valentine CJ,Szczpyka M,Smith CV

doi

10.1021/tx0000926

subject

Has Abstract

pub_date

2000-09-01 00:00:00

pages

873-82

issue

eissn

0893-228X

issn

1520-5010

pii

tx0000926

journal_volume

pub_type

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Effects of hepatotoxic doses of acetaminophen and furosemide on tissue concentrations of CoASH and CoASSG in vivo.