title: Mechanistic pathways of antioxidant cytoprotection by a novel IH636 grape seed proanthocyanidin extract.
abstract: To understand the bioavailability and mechanistic pathways of cytoprotection by IH636 grape seed proanthocyanidin extract (GSPE, commercially known as ActiVin) a series of in vitro and in vivo studies were conducted. Comparative protective abilities of GSPE, and vitamins C and E, singly and in combination, were assessed against smokeless tobacco extract (STE)-induced oxidative stress, DNA fragmentation and apoptotic cell death in a primary culture of normal human oral keratinocytes. GSPE protected against STE-induced oxidative stress, DNA damage and apoptotic cell death, and provided better protection as compared to vitamins C and E, singly and in combination. The bioavailability and protective ability of GSPE were examined against acetaminophen (AP)-induced hepato- and nephrotoxicity, amiodarone (AM)-induced lung toxicity, doxorubicin (DX)-induced cardiotoxicity and dimethylnitrosamine (DM)-induced spleenotoxicity in mice. GSPE-fed animals were compared with GSPE-untreated mice to evaluate the protective ability of GSPE against these structurally diverse drugs/chemicals. Serum chemistry changes, histopathology and DNA damage were evaluated. Results indicate that GSPE preexposure prior to the drugs/chemicals such as AP, AM, DX or DM treatment, provided near complete protection in terms of serum chemistry changes 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 in GSPE-fed animals. Histopathological examination of multiple target organs provided similar data. The results suggest that GSPE exposure is bioavailable and provides significant multiorgan protection against structurally diverse drug- and chemical-induced toxic assaults. Further, these studies exhibited a series of mechanistic information including free radical scavenging ability, anti-endonucleolytic activity, cytochrome P450 2E1 inhibitory activity, anti-necrotic, anti-apoptotic and anti-carcinogenic activities, modulatory effects on antioxidative and apoptotic regulatory genes such as Bcl2, c-myc and p53, which may be responsible for the novel chemoprotective properties exhibited by GSPE.
authors.affiliation: Creighton University School of Pharmacy & Allied Health Professions, Omaha, NE 68178, USA. debsis@creighton.edu
authors.forename: Debasis
authors.initials: D
authors.lastname: Bagchi
authors.forename: Sidhartha D
authors.initials: SD
authors.lastname: Ray
authors.forename: Manashi
authors.initials: M
authors.lastname: Bagchi
authors.forename: Harry G
authors.initials: HG
authors.lastname: Preuss
authors.forename: Sidney J
authors.initials: SJ
authors.lastname: Stohs
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects; D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000638:Amiodarone / Q000008:administration & dosage / Q000009:adverse effects; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001806:Blood Urea Nitrogen; D002453:Cell Cycle / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D004249:DNA Damage / Q000187:drug effects; D004128:Dimethylnitrosamine / Q000008:administration & dosage / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000009:adverse effects; D056604:Grape Seed Extract; D006331:Heart Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D015227:Lipid Peroxidation / Q000187:drug effects; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008813:Mice, Inbred ICR; D009336:Necrosis; D010084:Oxidation-Reduction; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D044945:Proanthocyanidins; D013154:Spleen / Q000293:injuries / Q000473:pathology; D014030:Tobacco, Smokeless / Q000009:adverse effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D018712:Analgesics, Non-Narcotic; D000970:Antineoplastic Agents; D000975:Antioxidants; D016166:Free Radical Scavengers; D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; D010936:Plant Extracts; D044945:Proanthocyanidins; D014665:Vasodilator Agents; D000082:Acetaminophen; D004317:Doxorubicin; D000410:Alanine Transaminase; D003402:Creatine Kinase; D004128:Dimethylnitrosamine; D000638:Amiodarone