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Interactions Between N-acetyl-p-benzoquinone Imine And Fluorescent Calcium Probes: Implications For Mechanistic Toxicology.

R. J. Riley, J. Leeder, H. M. Dosch, S. Spielberg
Published 1990 · Chemistry, Medicine

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Intracellular free calcium ([Ca2+]i) homeostasis has been implicated as an early target in both cellular necrosis and apoptosis. In this study, we have used peripheral blood mononuclear cells (PBMC) as target cells to investigate the effects of several reactive metabolites associated with drug toxicity on [Ca2+]i in order to delineate further early events in cytotoxicity. Compounds implicated in both drug-induced necrosis (N-acetyl-p-benzoquinone imine; NAPQI) and drug hypersensitivity (sulfamethoxazole hydroxylamine; SMX-HA) were examined and their effects on [Ca2+]i compared with those of the T cell mitogen phytohemagglutinin (PHA; 1.5 micrograms/ml) and the calcium ionophore ionomycin (2.5 microM). PHA and ionomycin produced characteristic elevations in [Ca2+]i as monitored by an increase in the fluorescence of fluo-3-loaded cells. SMX-HA did not significantly affect [Ca2+]i at concentrations previously shown to be cytotoxic to PBMC (100 and 500 microM), suggesting that Ca2+ homeostasis is not an early target for SMX-HA toxicity. Addition of NAPQI (250 microM) to fluo-3-loaded cells produced a marked decrease in fluorescence which was not reversed by ionomycin. Conversely, addition of NAPQI to cells loaded with indo-1 resulted in a rapid increase in fluorescence. This effect, however, was found to be attributable to NAPQI addition per se rather than to an increase in [Ca2+]i. HPLC and fluorescence analysis of samples generated from the decomposition of NAPQI revealed the presence of several products which fluoresced intensely at the excitation/emission wavelength pairs of a number of fluorescent probes commonly used to monitor [Ca2+]i.(ABSTRACT TRUNCATED AT 250 WORDS)
This paper references
10.1016/0278-6915(86)90172-9
Freshly isolated hepatocytes as a model for studying the toxicity of paracetamol.
A. Boobis (1986)
10.3109/10408448509037460
Enzymatic activation of chemicals to toxic metabolites.
F. P. Guengerich (1985)
10.1016/0300-483X(88)90196-5
Correlation between cytosolic Ca2+ concentration and cytotoxicity in hepatocytes exposed to oxidative stress.
P. Nicotera (1988)
10.1002/PATH.1711580314
Apoptosis—the mechanism of cell death in dimethylnitrosamine‐induced hepatotoxicity
D. Pritchard (1989)
10.1111/J.1365-2125.1988.TB05298.X
An in vitro study of the microsomal metabolism and cellular toxicity of phenytoin, sorbinil and mianserin.
R. J. Riley (1988)
Acetaminophen toxicity in human lymphocytes in vitro.
S. Spielberg (1980)
10.1080/15287397809529665
Toxic agents resulting from the oxidative metabolism of steroid hormones and drugs.
E. Horning (1978)
Horseradish peroxidase-catalyzed oxidation of acetaminophen to intermediates that form polymers or conjugate with glutathione.
D. W. Potter (1986)
10.1038/bjc.1972.33
Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics
J. Kerr (1972)
10.1042/BJ2480313
Fluorescence and bioluminescence measurement of cytoplasmic free calcium.
P. Cobbold (1987)
10.1096/fasebj.3.7.2497041
Calcium‐activated DNA fragmentation kills immature thymocytes
D. McConkey (1989)
10.1016/0009-2797(88)90052-X
Redox cycling and sulphydryl arylation; their relative importance in the mechanism of quinone cytotoxicity to isolated hepatocytes.
T. Gant (1988)
10.1016/0006-2952(85)90236-9
On the role of thiol groups in the inhibition of liver microsomal Ca2+ sequestration by toxic agents.
H. Thor (1985)
10.1016/s0021-9258(18)83166-0
Photochemically generated cytosolic calcium pulses and their detection by fluo-3.
J. Kao (1989)
10.1016/0014-5793(83)81180-6
Critical role of sulfhydryl group(s) in ATP‐dependent Ca2+ sequestration by the plasma membrane fraction from rat liver
G. Bellomo (1983)
Allergic reactions in man.
C. Parker (1982)
10.1016/0003-9861(89)90119-7
Glucocorticoids activate a suicide process in thymocytes through an elevation of cytosolic Ca2+ concentration.
D. McConkey (1989)
10.1007/BF00296939
Activation mechanisms to chemical toxicity
D. Parke (2004)
10.1016/0006-2952(80)90356-1
Inhibition of liver-microsome calcium pump by in vivo administration of CCl4, CHCl3 and 1,1-dichloroethylene (vinylidene chloride).
L. Moore (1980)
10.1016/s0021-9258(19)75736-6
The 1- and 2-electron oxidation of acetaminophen catalyzed by prostaglandin H synthase.
D. W. Potter (1987)
10.1016/0003-2697(89)90067-5
Fluorescence-based viability assay for studies of reactive drug intermediates.
J. Leeder (1989)
10.1016/s0021-9258(19)75735-4
Mechanisms of acetaminophen oxidation to N-acetyl-P-benzoquinone imine by horseradish peroxidase and cytochrome P-450.
D. Potter (1987)
10.1021/TX00007A008
On the role of Ca2+ in the toxicity of alkylating and oxidizing quinone imines in isolated hepatocytes.
P. Nicotera (1989)
10.1016/s0021-9258(18)32421-9
Inhibition of ATP-dependent microsomal Ca2+ sequestration during oxidative stress and its prevention by glutathione.
D. P. Jones (1983)
10.1016/s0021-9258(17)39003-8
Identification of acetaminophen polymerization products catalyzed by horseradish peroxidase.
D. W. Potter (1985)
10.1021/JM00350A001
Synthesis, decomposition kinetics, and preliminary toxicological studies of pure N-acetyl-p-benzoquinone imine, a proposed toxic metabolite of acetaminophen.
D. Dahlin (1982)
10.1016/0006-2952(87)90706-4
Drug disposition and drug hypersensitivity.
B. Park (1987)
Methods in Enzymology , Vol
S. Colowick (1966)
10.1016/0165-6147(89)90029-1
Role of Ca2+ in toxic cell killing.
S. Orrenius (1989)
10.1016/s0021-9258(17)38834-8
The toxicity of acetaminophen and N-acetyl-p-benzoquinone imine in isolated hepatocytes is associated with thiol depletion and increased cytosolic Ca2+.
M. Moore (1985)



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