ALCOHOL INTAKE AND RETINOID METABOLISM AND SIGNALING

酒精摄入量和视黄醇代谢及信号转导

• 批准号: 6711194
• 负责人: XIANG-DONG WANG
• 金额: $ 28万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6711194
• 关键词: JUN kinase; alcoholism /alcohol abuse; all trans retinol; behavioral /social science research tag; biological signal transduction; cell proliferation; chemical carcinogenesis; ethanol; hepatocellular carcinoma; laboratory rat; neoplasm /cancer nutrition therapy; nonhuman therapy evaluation; nutrition related tag; retinoids; vitamin metabolism

DESCRIPTION (provided by applicant): Our long-term objective is to study the +___________________________________ chemopreventive effect of retinoids on chronic and excessive alcohol related carcinogenesis in the liver and peripheral organs. The present grant proposal focuses on cell proliferation, which plays a central role in hepatic carcinogenesis in both the initiation and promotion stages, particularly when chemical carcinogens are involved. Retinoic acid plays an important role in controlling carcinogenic progression in a variety of cancers, including liver cancer. One of the chemopreventive effects of retinoids is thought to be mediated through control of proliferation via delaying progression of damaged cells into S phase, which allows for DNA repair and induction of apoptosis, thereby reducing the risk of carcinogenic initiation. However, long term and excessive ethanol intake reduces hepatic retinoid levels. The observation that retinoid concentrations are decreased in both plasma and cancerous liver tissues of hepatocarcinoma patients, suggests a role for retinoid depletion in hepatocarcinogenesis. However, it is not known 1) whether chronic ethanol-induced hepatocellular proliferation (which could convert hepatocytes from a state of resistance to a carcinogen to a state of susceptibility) is due to alcohol-impaired retinoid metabolism and signaling, and if so, 2) whether restoration of retinoid status by either inhibiting ethanol-induced retinoid catabolism or supplementing retinoic acid can suppress both ethanol-induced cell hyperproliferation as well as ethanol-promoted (diethylnitrosamine induced) hepatocellular carcinogenesis. We will investigate the possible role of diminished retinoid signaling and/or the up-regulation of the Jun N-terminal kinases-dependent (JNK) signaling pathway by chronic ethanol treatment on alcohol induced hepatocellular cell proliferation as well as alcohol-promoted hepatocellular carcinogenesis (induced by diethylnitrosamine). Simultaneously, we will test whether treatment with either chlormethiazole (an inhibitor of retinoic acid catabolism) and all-trans retinoic acid in ethanol-fed rats can inhibit alcohol-induced hepatocellular cell proliferation as well as alcohol-promoted hepatocellular carcinogenesis via either restoring normal retinoid signaling and/or inhibiting the JNK dependent signaling pathway. This study will be the first to link the regulation of retinoid signaling with Jun N-terminal kinases-dependent pathway, cell proliferation and apoptosis in an alcohol-treated, chemically induced carcinogenesis animal model, which would have implications for the prevention and treatment of alcohol related human cancers.

描述（由申请人提供）：我们的长期目标是研究 +_____________________________________ 类视黄素对慢性和酒精相关的化学预防作用 肝脏和外围器官中的致癌作用。目前的赠款提案 专注于细胞增殖，在肝脏中起着核心作用 在开始和促进阶段的癌变，尤其是 涉及化学致癌物。视黄酸在 控制各种癌症的致癌进展，包括肝脏 癌症。类维生素类似的化学预防作用之一被认为是 通过延迟受损的进展来控制增殖的介导 细胞进入S相，从而可以进行DNA修复和诱导凋亡， 从而降低了致癌启动的风险。但是，长期和 乙醇摄入过多可降低肝类视黄素水平。观察到 在血浆和癌性肝脏中，类视视视感性浓度均降低 肝癌患者的组织表明性类维生素的作用在 肝癌发生。但是，尚不清楚1）是否慢性 乙醇诱导的肝细胞增生（可能转化肝细胞 从抵抗状态到致癌的状态到易感性） 到达酒精受损的类维生素性代谢和信号传导，如果是，2）是否是否 通过抑制乙醇诱导的性类动物来恢复类维生素性状态 分解代谢或补充视黄酸可以抑制两个乙醇诱导的 细胞过度增殖以及乙醇促进（二乙基硝基胺） 诱导的）肝细胞癌。 我们将调查类维生素性信号传导下降和/或的可能作用 Jun N末端激酶（JNK）信号的上调 慢性乙醇在酒精诱导的肝细胞细胞上进行途径 增殖以及饮酒的肝细胞癌变 （由二乙基硝基胺诱导）。同时，我们将测试是否治疗 与甲甲唑（视黄酸分解代谢的抑制剂）和 乙醇喂养大鼠中的全反式视黄酸可以抑制酒精诱导的 肝细胞细胞增殖以及酒精促进的肝细胞 通过恢复正常的类维生素性信号传导和/或抑制的致癌作用 JNK依赖性信号通路。 这项研究将是第一个将类视感信号调节的调节与 Jun N末端激酶依赖性途径，细胞增殖和凋亡 经过酒精处理的化学诱导的致癌动物模型，该模型将 对与酒精相关的人类的预防和治疗有影响 癌症。

项目成果

Vitamin E supplementation does not prevent ethanol-reduced hepatic retinoic acid levels in rats.

补充维生素 E 并不能防止乙醇导致大鼠肝脏视黄酸水平降低。

• DOI: 10.1016/j.nutres.2009.09.008
• 发表时间: 2009
• 期刊: Nutrition research (New York, N.Y.)
• 作者: Chung,Jayong;Veeramachaneni,Sudipta;Liu,Chun;Mernitz,Heather;Russell,RobertM;Wang,Xiang-Dong
• 通讯作者: Wang,Xiang-Dong

Dietary tomato powder inhibits alcohol-induced hepatic injury by suppressing cytochrome p450 2E1 induction in rodent models.

• DOI: 10.1016/j.abb.2015.01.004
• 发表时间: 2015-04-15
• 期刊: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
• 影响因子: 3.9
• 作者: Stice, Camilla P.;Liu, Chun;Aizawa, Koichi;Greenberg, Andrew S.;Ausman, Lynne M.;Wang, Xiang-Dong
• 通讯作者: Wang, Xiang-Dong

Alcohol, vitamin A, and cancer.

• DOI: 10.1016/j.alcohol.2005.04.006
• 发表时间: 2005-04
• 期刊: Alcohol
• 影响因子: 2.3
• 作者: Xiang‐Dong Wang