Ginger Extract: Bioavailability Study and Lung Cancer Preventive Effect

描述(申请人提供)：本项目的目标是研究生姜提取物及其关键成分[6]-姜辣素和[6]-姜辣素的生物活性，并开发一种含有高浓度姜辣素的生姜提取物(GEHS)作为肺癌预防药物。生姜是生姜属植物的根茎，自古以来在中国、印度和阿拉伯国家作为草药使用。近年来，生姜因其抗氧化、抗炎、抗肿瘤等活性而受到广泛关注。生姜的主要成分是一系列辛辣的油树脂成分，称为姜酚，其中姜酚是主要成分。生姜还含有shogaol同系物，是在储存或热加工过程中相应的姜酚脱水形成的。在新鲜生姜中，几乎不能检测到shogaol。而在干姜中，在某些制剂中，shogaol的含量甚至可能高于姜酚。大多数研究人员认为姜辣素是其活性成分，对姜辣素的研究较少。我们最近的结果表明，[6]-姜辣素对肺癌和结肠癌细胞株的生长抑制活性比[6]-姜辣素更强(约10倍)。我们的假设是，生姜制剂中的主要活性成分可能是姜辣素，与其他生姜提取物相比，GEHS具有更强的防癌作用。1.研制GEHS制剂，研究GEHS给药后[6]-shogaol和[6]-gingerol的生物利用度和生物转化，寻找GEHS在小鼠体内研究的最佳剂量。2.在N-甲基-天冬氨酸(4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone，NNK)诱导的A/J小鼠肺癌模型中，测定地黄总皂苷、鲜姜提取物以及[6]-姜辣素和[6]-姜辣素对肺癌的抑制作用。我们相信，这一项目的结果将为生姜提取物中关键的抗癌活性成分提供基本信息。标准化和更具活性的生姜提取物制剂的开发将促进未来对生姜提取物健康益处的临床前和临床研究。 与公共健康相关：生姜作为调味品和药用已有数千年的历史。最近的研究表明，生姜具有抗氧化、抗炎和抗肿瘤活性。然而，目前还不清楚生姜中主要的抗肿瘤活性成分是什么。新鲜生姜的主要成分是一系列辛辣的油树脂成分，称为姜酚，[6]-姜酚是主要成分。而在干姜中，姜酚在热加工过程中的脱水产物shogaol是主要成分。在某些制剂中，它们的水平甚至可能高于姜辣素。大多数研究人员认为姜辣素是其活性成分，对姜辣素的研究较少。我们最近的结果表明，[6]-姜辣素对肺癌和结肠癌细胞株的生长抑制活性比[6]-姜辣素更强。在这个项目中，我们将开发和标准化高水平的生姜提取物(GEHS)，并研究[6]-shogaol和[6]-姜酚在GEHS中的生物利用度和生物转化，并与单独给药的化合物在小鼠身上的生物转化进行比较。此外，我们还将在NNK诱导的A/J小鼠肺癌模型中检测GEHS和新鲜生姜提取物以及[6]-shogaol和[6]-gingerol的抑制活性。NNK(4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone)是一种烟草致癌物，该模型与人类肺癌的形成密切相关。这些研究的结果将使以下方面成为可能：1)制定有效预防肺癌的生姜提取物的最佳制备工艺；2)为生姜补充剂的标准化提供科学依据，目的是进行化学预防保健声明；3)测定血浆和组织中的姜辣素和姜酚的水平，为了解化学预防效果提供依据；以及4)通过使用标准化提取物和开发生姜制品消费的暴露生物标志物，提高未来化学预防效果临床试验的质量。

DESCRIPTION (provided by applicant): The objective of this project is to study the biological activities of ginger extract and its key constituents, [6]-gingerol and [6]-shogaol, and develop a ginger extract with high level of shogaols (GEHS) as a lung cancer preventive agent. Ginger, the rhizome of the plant Zingiber officinale, has been used as a herbal medicine in China, India, and Arabic countries since ancient times. Recently, ginger has received extensive attention due to its anti-oxidant, anti-inflammatory, and anti-tumor activities. The main principles in ginger are the series of pungent oleoresin constituents known as gingerols, with [6]-gingerol being the major component. Ginger also contains shogaol homologues that are formed by dehydration of corresponding gingerols during storage or thermal processing. In fresh ginger, very little shogaols can be detected. Whereas in dried ginger, the levels of shogaols can be even higher than gingerols in some preparations. Most researchers have considered gingerols as the active principles and have paid little attention to shogaols. Our recent results showed that [6]- shogaol has greater growth inhibitory activity (about 10 fold) on lung and colon cancer cell lines than [6]- gingerol. Our hypothesis is that shogaols can be the major active constituents of ginger preparations and GEHS has stronger cancer preventive effect than other ginger extracts. The specific aims are: 1. To develop a GEHS preparation, study the bioavailability and biotransformation of [6]-shogaol and [6]-gingerol after administration of GEHS to mice, and find the optimal doses of GEHS for studies in mice. 2. To determine the inhibitory activities of GEHS and extract from fresh ginger (EFG) as well as [6]- shogaol and [6]-gingerol in a 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis model in A/J mice. We believe that results from this project will provide the basic information on key active cancer preventive constituents in ginger extracts. The development of a standardized and a more active ginger extract preparation will facilitate future pre-clinical and clinical studies on the health benefit of ginger extracts. PUBLIC HEALTH RELEVANCE: Ginger has been cultivated for thousands of years as a spice and for medicinal purposes. Recent studies have shown that ginger has antioxidant, anti-inflammatory, and anti-tumor activities. However, it is unclear what the major active anti-tumor components in ginger are. The main principles in fresh ginger are the series of pungent oleoresin constituents known as gingerols, with [6]-gingerol being the major component. Whereas in dried ginger, shogaols, the dehydration products of gingerols during thermal processing, are predominant components. Their levels can be even higher than gingerols in some preparations. Most researchers have considered gingerols as the active principles and have paid little attention to shogaols. Our recent results showed that [6]-shogaol has greater growth inhibitory activity on lung and colon cancer cell lines than [6]-gingerol. In this project, we will develop and standardize ginger extract with high levels of shogaols (GEHS), and study the bioavailability and biotransformation of [6]-shogaol and [6]-gingerol in GEHS in comparison to that of the compound administered alone in mice. Furthermore, we will determine the inhibitory activities of GEHS and extract from fresh ginger, as well as [6]-shogaol and [6]-gingerol in a NNK-induced lung carcinogenesis model in A/J mice. NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone) is a tobacco carcinogen, and this model is highly relevant to human lung cancer formation. Results from these studies will make it possible to 1) develop an optimal preparation process of ginger extract that will be effective in the prevention of lung cancer; 2) provide a scientific basis for standardization of ginger supplements aim to make chemoprevention health claims; 3) determine the plasma and tissue levels of shogaols and gingerols which provide basis for understanding the chemopreventive effects; and 4) improve the quality of future clinical trials on chemopreventive effect through use of standardized extracts and the development of exposure biomarkers for the consumption of ginger products.