The Role of Cytochrome P450 1B1 in Dibenzo[ a,l ]pyrene-induced Carcinogenesis

In human cells, the most carcinogenic polycyclic aromatic hydrocarbon dibenzo[ a,l ]pyrene (DB[ a,l ]P) forms high levels of DNA adducts through formation of the ( m )- anti -(11 R ,12 S )-diol (13 S ,14 R )-epoxide (DB[ a,l ]PDE) and its metabolic precursor, the ( m )-(11 R ,12 R )-diol. Generation of these adducts results from the catalytic activity of cytochrome P450 (P450) 1A1 and 1B1. Additional adducts such as (+)- syn -DB[ a,l ]PDE-DNA or more polar DNA adducts were detected only after increasing exposure doses of the parent compound or in cells that express P450 1A1. At low concentrations (·;100 nM) exclusively ( m )- anti -DB[ a,l ]PDE-DNA adducts were formed by P450 1B1, which is constitutively expressed in many mammalian tissues. Measurement of DNA binding and mutagenicity of DB[ a,l ]P in V79 cells expressing human P450 enzymes revealed a higher activity of P450 1B1 compared to 1A1 at low concentrations. Treatment of P450 1B1 knockout mice and DNA binding studies with fibroblasts isolated from these animals provided further evidence for the central role of P450 1B1-catalyzed formation of ( m )- anti -DB[ a,l ]PDE-DNA adducts in DB[ a,l ]P-induced carcinogenesis.     

辐射防护的生物学基础

作为辐射防护生物学基础的放射生物学效应，近年来有了很大进展。本文第一部分扼要的回顾并展望了这方面的三个重点：小剂量（低剂量率）照射效应及其危险的评估；辐射致癌研究的发展，包括：靶分子、单细胞起源、发展的多阶段、肿瘤的相关基因及辐射致癌的特性；遗传效应，以多因素疾患为重点，介绍了突变份额的概念及应用。第二部分是本实验室的研究工作，以α粒子照射诱发的不同细胞（ＳＨＥ，大鼠气管上皮细胞，人支气管上皮细胞等）恶性转化为模型，研究了恶转过程中，细胞的生物学特征，染色体畸变规律，癌基因、抑癌基因的变异与正负调控，以及通过差异显示分析探索与恶转相关的新基因，并应用临床肺癌标本进行了基因的分析。实验中已克隆到２４个与α粒子诱发恶性转化的相关ｃＤＮＡ片断，其中１３个为新的，已登录到ＧｅｎＢａｎｋ，初步找到一个３．５ｋｂ的新基因，正在进一步研究中。     

Folate and colorectal cancer: an evidence-based critical review

Currently available evidence from epidemiologic, animal, and intervention studies does not unequivocally support the role of folate, a water-soluble B vitamin and important cofactor in one-carbon transfer, in the development and progression of colorectal cancer (CRC). However, when the portfolio of evidence from these studies is analyzed critically, the overall conclusion supports the inverse association between folate status and CRC risk. It is becoming increasingly evident that folate possesses dual modulatory effects on colorectal carcinogenesis depending on the timing and dose of folate intervention. Folate deficiency has an inhibitory effect whereas folate supplementation has a promoting effect on the progression of established colorectal neoplasms. In contrast, folate deficiency in normal colorectal mucosa appears to predispose it to neoplastic transformation, and modest levels of folic acid supplementation suppress, whereas supraphysiologic supplemental doses enhance, the development of cancer in normal colorectal mucosa. Several potential mechanisms relating to the disruption of one-carbon transfer reactions exist to support the dual modulatory role of folate in colorectal carcinogenesis. Based on the lack of compelling supportive evidence and on the potential tumor-promoting effect, routine folic acid supplementation should not be recommended as a chemopreventive measure against CRC at present.     

辐射免疫学研究的某些进展

本文综述了辐射免疫效应研究中的若干进展,着重点是辐射免疫学与辐射致癌的关系。文中第一部分讨论了淋巴细胞的放射敏感性,强调淋巴细胞群体的异质性,不同淋巴细胞亚群及其亚组的相对放射敏感性,以及激活状态对淋巴细胞放射敏感性的影响。第二部分涉及免疫监视学说的要点,抗肿瘤免疫的特异和非特异成分,以及辐射对它们的影响。第三部分是关于辐射引起的免疫增强现象和辐射刺激作用在免疫系统的表现,并简述了著者实验室有关辐射刺激作用的某些资料。文章强调指出需要对低水平辐射对免疫系统和其它防御适应功能可能引起的刺激作用及其机制进行更细致的研究。     

Effects of DMBA Preparation on DMBA-Induced Rat Mammary Carcinogenesis

We compared two protocols for 7,12-dimethylbenz[ a ]anthracene (DMBA)-induced mammary carcinogenesis. DMBA (20 mg/ml) was prepared at room temperature or at 60°C and administered by gavage to 50-day-old Sprague-Dawley rats. Two days post-DMBA, mammary epithelial DNA was 32 P-postlabeled. At 12 weeks post-DMBA, tumor DNA was screened for H- ras codon 61 mutations using an enriched polymerase chain reaction (EPCR). The number of in situ carcinomas (3.0 - 2.7 vs. 2.5 - 2.7), invasive carcinomas (1.1 - 1.6 vs. 0.6 - 0.8), and H- ras codon 61 mutations (34 - 13% vs. 23 - 13%) were statistically not different ( p = 0.05) between the groups. The relative adduct levels in mammary organoids were significantly ( p h 0.001) greater in the 60°C (568 - 158) than the room temperature (150 - 130) group. While DMBA-DNA adduct levels differed significantly between these protocols, this did not correlate with significant differences in tumor pathologies or H- ras codon 61 mutations.     

BEIR V 辐射致癌危险系数估算的方法和结果

本文简要介绍1990年发表的 BEIR V 报告的辐射致癌危险估计模型及其计算结果。与 BEIR Ⅲ报告相比较,资料的随访时间又有延长,在方法学上的重要变化是使用新的剂量体系 DS86,不再使用原来的恒定预测模型,通过多因素分析技术增加了某些时间变量对危险估计的修饰作用,对不同类别的癌症分别使用不同的模型和参数。计算后给出一次急性照射(0.1 Sv)的癌症死亡危险系数是7.9×10~(-2)Sv~(-1),与 UNSCEAR1988年报告结果相似。但是,BEIR V 认为在把这个结果用于估计低剂量照射危险时没有必要再使用剂量率校正因子。     

Dietary Lipids Impacts on Healthy Ageing

Healthy ageing is gaining attention in the lipid nutrition field. As in vivo biomarkers of healthy ageing, we have evaluated the survival, learning/memory performance, and physical potencies in rodents fed a diet supplemented with high-linoleic acid (LNA, ω6) safflower oil or high-α-linolenic acid (ALA, ω3) perilla oil for long periods. The results suggested that perilla oil with a low ω6/ω3 ratio is beneficial for healthy ageing. In order to address this issue further, we determined the survival of stroke-prone SHR (SHRSP) rats fed a conventional rodent diet supplemented with 10% fat or oil. Survival was longer with ω3-rich oils compared with ω6-rich oils. However, some kinds of vegetable oils and hydrogenated oils shortened the survival of SHRSP rats to an unusual degree (ca. 40% compared with that of ω6-rich oil) that could not be accounted for by the fatty acid and phytosterol composition of the oils. The observed decrease in platelet counts was associated with pathological changes in the kidney and other organs. Dihydro-vitamin K1 is proposed as a likely candidate as a stroke-stimulating factor in hydrogenated oils. Thus, factors other than fatty acids (ω6/ω3 balance) and phytosterols must be taken into account when fats and oils are evaluated in relation to healthy ageing.     

抗肿瘤发生与辐射防护研究现状

1987年3月8～12日在美国Gajthersburg召开了第二届国际抗肿瘤发生及辐射防护会议。发起单位是美国国家标准局(National Bureau of.Standard,NBS),环境保护机构(EnviromentalProtection Agency),国立癌症研究所(National Cancer Institute)以及国家辐射防护委员会(National Council for Radiation Protection)。 会议旨在交流肿瘤预防的机理研究,以及在分子生物学及自由基化学进展基础上的肿瘤治疗情况,共分八大部分。每一部分由三到六位学者口头发言、讨论以及相应的科学墙报所组成。本文选择一些有兴趣的内容作下述介绍。     

致癌染料——致癌染料的识别

论述了从染料、中间体化学结构和中间体同素异构体化学结构识别染料致癌性的方法；详细地介绍了常用各大类染料中的致癌及可能致癌染料品种。