Bagchi Debasis, Ray Sidhartha D, Bagchi Manashi, Preuss Harry G, Stohs Sidney J
Creighton University School of Pharmacy & Allied Health Professions, Omaha, NE 68178, USA.
Indian J Exp Biol. 2002 Jun;40(6):717-26.
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.
为了解IH636葡萄籽原花青素提取物（GSPE，商品名为ActiVin）的生物利用度和细胞保护作用机制，开展了一系列体外和体内研究。评估了GSPE以及维生素C和E单独使用及联合使用时，对无烟烟草提取物（STE）诱导的正常人口腔角质形成细胞原代培养物中的氧化应激、DNA片段化和凋亡性细胞死亡的比较保护能力。GSPE可抵御STE诱导的氧化应激、DNA损伤和凋亡性细胞死亡，并且与单独及联合使用的维生素C和E相比，提供了更好的保护。研究了GSPE对小鼠中对乙酰氨基酚（AP）诱导的肝毒性和肾毒性、胺碘酮（AM）诱导的肺毒性、阿霉素（DX）诱导的心脏毒性以及二甲基亚硝胺（DM）诱导的脾毒性的生物利用度和保护能力。将喂食GSPE的动物与未处理的小鼠进行比较，以评估GSPE对这些结构各异的药物/化学物质的保护能力。评估了血清化学变化、组织病理学和DNA损伤情况。结果表明，在诸如AP、AM、DX或DM等药物/化学物质处理之前预先暴露于GSPE，在血清化学变化以及抑制凋亡和坏死这两种细胞死亡形式方面提供了近乎完全的保护。在喂食GSPE的动物中，这些药物引发的各种组织中的DNA损伤显著减少。多个靶器官的组织病理学检查提供了类似的数据。结果表明，暴露于GSPE具有生物利用度，并对结构各异的药物和化学物质诱导的毒性攻击提供显著的多器官保护。此外，这些研究展示了一系列机制信息，包括自由基清除能力、抗核酸内切酶活性、细胞色素P4５０ 2E1抑制活性、抗坏死、抗凋亡和抗癌活性，以及对诸如Bcl2、c-myc和p53等抗氧化和凋亡调节基因的调节作用，这些可能是GSPE所展现的新型化学保护特性的原因。
