Wang X D, Liu C, Bronson R T, Smith D E, Krinsky N I, Russell M
Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University and Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA.
J Natl Cancer Inst. 1999 Jan 6;91(1):60-6. doi: 10.1093/jnci/91.1.60.
Epidemiologic studies have demonstrated that individuals who eat more fruits and vegetables and/or have high levels of serum beta-carotene have a lower risk of cancer, especially lung cancer. However, recent human intervention studies using beta-carotene supplements have shown an increase in the risk of lung cancer among smokers and asbestos workers. In this study, we used an animal model system to evaluate the hazard associated with a combination of high-dose beta-carotene supplementation and tobacco smoking.
Ferrets were given a beta-carotene supplement, exposed to cigarette smoke, or both for 6 months. Cell proliferation and squamous metaplasia in lung tissue were assessed by examination of proliferating-cell nuclear antigen expression and histopathologic examination, respectively. beta-Carotene and retinoid concentrations in lung tissue and plasma samples were analyzed by high-performance liquid chromatography. Expression of genes for retinoic acid receptors (RARs) and activator protein-1 (encoded by the c-Jun and c-Fos genes) in lung tissue specimens was examined by western blotting.
A strong proliferative response in lung tissue and squamous metaplasia was observed in all beta-carotene-supplemented animals, and this response was enhanced by exposure to tobacco smoke. When compared with control groups, all three treatment groups had statistically significantly lower concentrations of retinoic acid in lung tissue, and they exhibited 18%-73% reductions in RARbeta gene expression; however, RARalpha and RARgamma gene expression was not reduced. Ferrets given a beta-carotene supplement and exposed to tobacco smoke had threefold to fourfold elevated expression of the c-Jun and c-Fos genes.
Diminished retinoid signaling, resulting from the suppression of RARbeta gene expression and overexpression of activator protein-1, could be a mechanism to enhance lung tumorigenesis after high-dose beta-carotene supplementation and exposure to tobacco smoke.
流行病学研究表明，摄入更多水果和蔬菜及/或血清β-胡萝卜素水平较高的个体患癌风险较低，尤其是肺癌。然而，近期使用β-胡萝卜素补充剂的人体干预研究显示，吸烟者和石棉工人患肺癌的风险增加。在本研究中，我们使用动物模型系统评估高剂量β-胡萝卜素补充剂与吸烟联合使用所带来的危害。
雪貂接受β-胡萝卜素补充剂、接触香烟烟雾或两者同时进行处理，持续6个月。分别通过检测增殖细胞核抗原表达和组织病理学检查来评估肺组织中的细胞增殖和鳞状化生。通过高效液相色谱法分析肺组织和血浆样本中的β-胡萝卜素和类视黄醇浓度。通过蛋白质印迹法检测肺组织标本中视黄酸受体（RARs）和活化蛋白-1（由c-Jun和c-Fos基因编码）的基因表达。
在所有补充β-胡萝卜素的动物中均观察到肺组织强烈的增殖反应和鳞状化生，且接触香烟烟雾会增强这种反应。与对照组相比，所有三个处理组肺组织中的视黄酸浓度在统计学上均显著降低，并且它们的RARβ基因表达降低了18%-73%；然而，RARα和RARγ基因表达并未降低。接受β-胡萝卜素补充剂并接触香烟烟雾的雪貂，其c-Jun和c-Fos基因表达升高了三到四倍。
RARβ基因表达受抑制和活化蛋白-1过表达导致的类视黄醇信号减弱，可能是高剂量β-胡萝卜素补充剂与接触香烟烟雾后增强肺肿瘤发生的一种机制。
