Protection against drug- and chemical-induced multiorgan toxicity by a novel IH636 grape seed proanthocyanidin extract.
Grape seed proanthocyanidins have been demonstrated to exhibit a broad spectrum of pharmacological, therapeutic and chemoprotective properties. In our previous studies, IH636 grape seed proanthocyanidin extract (GSPE, commercially known as ActiVin) demonstrated excellent concentration- and dose-dependent free radical scavenging abilities in both in vitro and in vivo models and provided significantly better protection than vitamins C, E and beta-carotene. GSPE demonstrated significant cytotoxicity towards human breast, lung and gastric adenocarcinoma cells, while enhancing the growth and viability of normal human gastric mucosal cells and macrophage J774A.1 cells. In this study, the bioavailability and protective ability of GSPE were examined against acetaminophen-induced hepatoxicity, amiodarone-induced pulmonary toxicity, doxorubicin-induced cardiotoxicity, cadmium chloride-induced nephrotoxicity, dimethylnitrosamine-induced spleenotoxicity and O-ethyl-S,S-dipropyl phosphorodithioate (MOCAP)-induced neurotoxicity in mice. In each experiment, half of the test animals were orally fed GSPE for 7-10 days prior to drug/chemical exposure, while the other half received no GSPE. Parameters of analysis included changes in serum chemistry [alanine amino-transferase (ALT), blood urea nitrogen and creatine kinase], histopathology and integrity of genomic DNA. The results indicated that GSPE preexposure prior to the drugs/chemicals such as acetaminophen, amiodarone, doxorubicin, cadmium chloride or dimethylnitrosamine treatment, provided near complete protection in terms of serum chemistry changes (ALT, blood urea nitrogen and creatine kinase) and inhibition of both forms of cell death, e.g., apoptosis and necrosis. DNA damage in various tissues triggered by these agents was significantly reduced. Histopathological examination of the organs evaluated reflected similar patterns to those of the serum chemistry and DNA results. MOCAP exposure showed symptoms of severe neurotoxicity coupled with serum chemistry changes in the absence of any significant genomic change or brain pathology. GSPE afforded only partial protection in the brain tissue. These results suggest that GSPE exposure is bioavailable and provides significant multiorgan protection against drug- and chemical-induced toxic assaults.
Creighton University School of Pharmacy and Allied Health Professions, Omaha, Nebraska, USA. debsis@creighton.edu
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D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001682:Biological Availability; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000517:prevention & control; D056486:Chemical and Drug Induced Liver Injury; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D053938:DNA Fragmentation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control*; D005260:Female; D016166:Free Radical Scavengers / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D056604:Grape Seed Extract; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control; D008107:Liver Diseases / Q000517:prevention & control; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D051379:Mice; D010936:Plant Extracts / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D044945:Proanthocyanidins; D013154:Spleen / Q000293:injuries / Q000473:pathology
D000975:Antioxidants; D016166:Free Radical Scavengers; D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; D010936:Plant Extracts; D044945:Proanthocyanidins; D000410:Alanine Transaminase