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PJ34, a Poly Adenosine Diphosphate‐Ribose Polymerase Inhibitor, Attenuates Chromate‐Induced Nephrotoxicity
Author(s) -
YamCanul Paola,
Chirino Yolanda Irasema,
SánchezGonzález Dolores Javier,
MartínezMartínez Claudia María,
Cruz Cristino,
PedrazaChaverri José
Publication year - 2008
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2008.00224.x
Subject(s) - nephrotoxicity , oxidative stress , poly adp ribose polymerase , chemistry , malondialdehyde , parp inhibitor , glutathione peroxidase , ebselen , pharmacology , antioxidant , biochemistry , endocrinology , enzyme , superoxide dismutase , medicine , toxicity , polymerase , organic chemistry
Potassium dichromate (K 2 Cr 2 O 7 )‐induced nephrotoxicity is associated with oxidative stress. In addition, the activation of the polyadenosine diphosphate‐ribose [poly(ADP‐ribose)] polymerase‐1 (PARP‐1) plays a role in the pathophysiology of some diseases associated with oxidative stress. To clarify the potential role of PARP‐1 in this experimental model, N‐(6‐oxo‐5,6‐dihydro‐phenanthridin‐2‐yl)‐N,N‐dimethyacetamide HCl (PJ34), a highly specific inhibitor of this enzyme, was used. Nephrotoxicity was induced in rats by a single sc injection of K 2 Cr 2 O 7 ; studies were performed 2 days later. PJ34 was given intraperitoneally (15 mg/kg) 1 hr before and 1, 5, 24, 26, 31 and 46 hr after K 2 Cr 2 O 7 injection. Nephrotoxicity was evaluated by histological analysis and by measuring blood urea nitrogen, serum creatinine, serum glutathione peroxidase activity and urinary excretion of N‐acetyl‐β‐ d ‐glucosaminidase. PARP‐1 activation was evaluated by the immunostaining of poly(ADP‐ribose). In addition, the following markers of oxidative stress were evaluated: 3‐nitrotyrosine, 4‐hydroxy‐2‐nonenal, malondialdehyde and protein carbonyl content. K 2 Cr 2 O 7 increased poly(ADP‐ribose) content suggesting the PARP‐1 activation in this model. PJ34 significantly ameliorated the K 2 Cr 2 O 7 ‐induced: (i) nephrotoxicity, (ii) poly(ADP‐ribose) accumulation and (iii) oxidative stress. It is concluded that PARP‐1 is activated and involved, at least in part, in K 2 Cr 2 O 7 ‐induced nephrotoxicity in rats.