Kensler Thomas W, Egner Patricia A, Agyeman Abena S, Visvanathan Kala, Groopman John D, Chen Jian-Guo, Chen Tao-Yang, Fahey Jed W, Talalay Paul
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Top Curr Chem. 2013;329:163-77. doi: 10.1007/128_2012_339.
Sulforaphane is a promising agent under preclinical evaluation in many models of disease prevention. This bioactive phytochemical affects many molecular targets in cellular and animal models; however, amongst the most sensitive is Keap1, a key sensor for the adaptive stress response system regulated through the transcription factor Nrf2. Keap1 is a sulfhydryl-rich protein that represses Nrf2 signaling by facilitating the polyubiquitination of Nrf2, thereby enabling its subsequent proteasomal degradation. Interaction of sulforaphane with Keap1 disrupts this function and allows for nuclear accumulation of Nrf2 and activation of its transcriptional program. Enhanced transcription of Nrf2 target genes provokes a strong cytoprotective response that enhances resistance to carcinogenesis and other diseases mediated by exposures to electrophiles and oxidants. Clinical evaluation of sulforaphane has been largely conducted by utilizing preparations of broccoli or broccoli sprouts rich in either sulforaphane or its precursor form in plants, a stable β-thioglucose conjugate termed glucoraphanin. We have conducted a series of clinical trials in Qidong, China, a region where exposures to food- and air-borne carcinogens has been considerable, to evaluate the suitability of broccoli sprout beverages, rich in either glucoraphanin or sulforaphane or both, for their bioavailability, tolerability, and pharmacodynamic action in population-based interventions. Results from these clinical trials indicate that interventions with well characterized preparations of broccoli sprouts may enhance the detoxication of aflatoxins and air-borne toxins, which may in turn attenuate their associated health risks, including cancer, in exposed individuals.
萝卜硫素是一种很有前景的物质，正在多种疾病预防模型中进行临床前评估。这种生物活性植物化学物质在细胞和动物模型中影响许多分子靶点；然而，其中最敏感的是Keap1，它是通过转录因子Nrf2调节的适应性应激反应系统的关键传感器。Keap1是一种富含巯基的蛋白质，通过促进Nrf2的多聚泛素化来抑制Nrf2信号传导，从而使其随后被蛋白酶体降解。萝卜硫素与Keap1的相互作用破坏了这种功能，使Nrf2在细胞核中积累并激活其转录程序。Nrf2靶基因转录增强引发强烈的细胞保护反应，增强对致癌物和其他由接触亲电试剂和氧化剂介导的疾病的抵抗力。萝卜硫素的临床评估主要是通过使用富含萝卜硫素或其植物前体形式（一种稳定的β-硫代葡萄糖共轭物，称为萝卜硫苷）的西兰花或西兰花芽提取物进行的。我们在中国启东进行了一系列临床试验，启东是一个食物和空气中致癌物暴露相当严重的地区，以评估富含萝卜硫苷或萝卜硫素或两者的西兰花芽饮料在人群干预中的生物利用度、耐受性和药效学作用的适用性。这些临床试验的结果表明，用特征明确的西兰花芽提取物进行干预可能会增强黄曲霉毒素和空气传播毒素的解毒作用，这反过来可能会降低暴露个体中包括癌症在内的相关健康风险。
