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Titolo:
Ca2+-calmodulin antagonist chlorpromazine and poly(ADP-Ribose) polymerase modulators 4-aminobenzamide and nicotinamide influence hepatic expression of bcl-XL and p53 and protect against acetaminophen-induced programmed and unprogrammed cell death in mice
Autore:
Ray, SD; Balasubramanian, G; Bagchi, D; Reddy, CS;
Indirizzi:
Long Isl Univ, AMS Coll PHarm & Hlth Sci, Div Pharmacol Toxicol & Med Chem, Mol Toxicol Program, Brooklyn, NY 11201 USA Long Isl Univ Brooklyn NY USA 11201 xicol Program, Brooklyn, NY 11201 USA Univ Missouri, Dept Vet Biomed Sci, Columbia, MO 65211 USA Univ Missouri Columbia MO USA 65211 et Biomed Sci, Columbia, MO 65211 USA
Titolo Testata:
FREE RADICAL BIOLOGY AND MEDICINE
fascicolo: 3, volume: 31, anno: 2001,
pagine: 277 - 291
SICI:
0891-5849(20010801)31:3<277:CACAPP>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
TUMOR-SUPPRESSOR P53; INDUCED LIVER-INJURY; DNA-DAMAGE; HYDROGEN-PEROXIDE; IN-VIVO; PERMEABILITY TRANSITION; LIPID-PEROXIDATION; MAMMALIAN-CELLS; RAT HEPATOCYTES; MOUSE-LIVER;
Keywords:
acetaminophen; apoptosis; bcl-XL; p53; poly(ADP-ribose)polymerase; chlorpromazine; 4-aminobenzamide; nicotinamide; DNA-repair; free radicals;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
69
Recensione:
Indirizzi per estratti:
Indirizzo: Ray, SD Long Isl Univ, AMS Coll PHarm & Hlth Sci, Div Pharmacol Toxicol & Med Chem, Mol Toxicol Program, 75 Dekalb Ave, Brooklyn, NY 11201 USA Long Isl Univ 75 Dekalb Ave Brooklyn NY USA 11201 yn, NY 11201 USA
Citazione:
S.D. Ray et al., "Ca2+-calmodulin antagonist chlorpromazine and poly(ADP-Ribose) polymerase modulators 4-aminobenzamide and nicotinamide influence hepatic expression of bcl-XL and p53 and protect against acetaminophen-induced programmed and unprogrammed cell death in mice", FREE RAD B, 31(3), 2001, pp. 277-291

Abstract

Acetaminophen (AAP), the analgesic hepatotoxicant, is a powerful inducer of oxidative stress, DNA fragmentation, and apoptosis. The anti-apoptotic oncogene bcl-XL, and the pro-apoptotic oncogene p53 are two key regulators ofcell cycle progression and/or apoptosis subsequent to DNA damage in vitro and in vivo. This study investigated the effect of AAP on the expression ofthese oncogenes and whether agents that modulate DNA fragmentation (chlorpromazine, CPZ) and DNA repair through poly(ADP-Ribose) polymerase (PAR-P) activity (4-AB: 4-aminobenzamide) can protect against AAP-induced hepatotoxicity by inhibiting oxidative stress, DNA fragmentation, and/or by altering the expression of bcl-XL and p53. In addition, the protective effect of supplemental nicotinamide (NICO), known to be depleted in cells with high PARPactivity during DNA repair, is similarly evaluated. Male ICR mice (3 months old) were administered vehicle alone; nontoxic doses of 4-AB (400 mg/kg, ip), NICO (250 mg/kg, ip) or CPZ (25 mg/kg, ip), hepatotoxic dose of AAP alone (500 mg/kg, ip), or AA-P plus one of the protective agents 1 h later. All animals were sacrificed 24 h following AA-P administration. Serum alanine aminotransferase, activity (ALT), hepatic histopathology and lipid peroxidation, DNA damage, and expression of bcl-XL and p53 (western blot analysis) were compared in various groups. All of the three agents significantly prevented AAP-induced liver injury, lipid peroxidation, DNA damage, and associated apoptotic and necrotic cell deaths, 4-AB being the most effective andNICO the least. Compared to control, there was a considerable decrease in bcl-XL expression, and an increase in p53 expression in AAP-exposed livers. The effect of AAP on bcl-XL was antagonized and that on p53 was synergizedby the PARP-modulator 4-AB as well as NICO, whereas the endonuclease inhibitor CPZ was without effect on either bcl-XL or p53 expression. These results suggest that the hepatotoxic effect of AA-P involves multiple mechanismsincluding oxidative stress, upregulation. of endonuclease (or cas ase-activated DNAse) and alteration of pro- and anti-apoptotic oncogenes. The observed antagonism of AAP-induced hepatocellular apoptosis and/or necrosis by modulators of multiple processes including DNA repair suggests the likelihood that a more effective therapy against AAP intoxication should involve a combination of antidotes. (C) 2001 Elsevier Science Inc.

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Documento generato il 24/11/20 alle ore 09:37:30