Probucol as a potent inhibitor of oxygen radical-induced lipid peroxidation and DNA damage: in vitro studies.
Probucol, a clinically used cholesterol lowering and antioxidant drug, was investigated for possible protection against lipid peroxidation and DNA damage induced by iron nitrilotriacetate (Fe-NTA) plus hydrogen peroxide (H2O2). Fe-NTA is a potent nephrotoxic agent and induces acute and subacute renal proximal tubular necrosis by catalyzing the decomposition of H2O2-derived production of hydroxyl radicals, which are known to cause lipid peroxidation and DNA damage. Fe-NTA is associated with a high incidence of renal adenocarcinoma in rodents. Lipid peroxidation and DNA damage are the principal manifestation of Fe-NTA induced toxicity, which could be mitigated by probucol. Incubation of renal microsomal membrane and/or calf thymus DNA with H2O2 (40 mM) in the presence of Fe-NTA (0.1 mM) induces renal microsomal lipid peroxidation and DNA damage to about 2.4-fold and 5.9-fold, respectively, as compared to control (P < 0.05). Induction of renal microsomal lipid peroxidation and DNA damage was inhibited by probucol in a concentration-dependent manner. In lipid peroxidation protection studies, probucol treatment showed a concentration-dependent inhibition (10-34% inhibition; P < 0.05) of Fe-NTA plus H2O2-induced lipid peroxidation as measured by thiobarbituric acid reacting species' (TBARS) formation in renal microsomes. Similarly, in DNA damage protection studies, probucol treatment also showed a concentration-dependent strong inhibition (36-71% inhibition; P < 0.05) of DNA damage. From these studies, it was concluded that probucol inhibits peroxidation of microsomal membrane lipids and DNA damage induced by Fe-NTA plus H2O2. However, because the lipid peroxidation and DNA damage studied here are regarded as early markers of carcinogenesis, we suggest that probucol may be developed as a cancer chemopreventive agent against renal carcinogenesis and other adverse effects of Fe-NTA exposure in experimental animals, in addition to being a cholesterol-lowering drug, useful for the control of hypercholestrolemia.
Department of Pathological Research, Faculty of Medicine, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Mohammad
M
Iqbal
Som Datta
SD
Sharma
Shigeru
S
Okada
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D004249:DNA Damage; D005290:Ferric Compounds / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D011341:Probucol / Q000737:chemistry / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000975:Antioxidants; D002273:Carcinogens; D005290:Ferric Compounds; D005609:Free Radicals; D016877:Oxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D009571:Nitrilotriacetic Acid; D011341:Probucol; C020326:ferric nitrilotriacetate