健康人人关心的话题分享 http://blog.sciencenet.cn/u/qpzeng 写“正能量”博客,做“富营养”科普

博文

喝酒致癌再添新“铁证”?

已有 2557 次阅读 2017-6-26 14:21 |个人分类:期刊论文|系统分类:论文交流|关键词:喝酒,致癌

喝酒究竟能不能致癌?这是一个问题;喝酒究竟有益还是有害?这又是另一个问题。对于后一个问题,相信大家的看法比较一致:适量饮酒有益健康,过量饮酒(酗酒)有害健康。可是,对于前一个问题,众说纷纭,不成定论。最近一则新闻在网上流传,大家可以了解一下。


喝酒上脸的同志也需好好看看:英国剑桥科学家阐释甲醛致癌机制


英国剑桥大学的科学家本月在《细胞》杂志上发布了一项研究,阐述了BRCA2突变是如何受到环境因素——甲醛的影响,从而导致癌症发生的!

这个研究针对的不只是女性男性朋友们也千万不要掉以轻心,因为虽然BRCA2突变导致的前列腺癌通常在老年时期才会发生,但是具有BRCA2突变的男性患乳腺癌的概率可是要比BRCA1突变的男性明显增加的[3]。

剑桥大学医学研究委员会癌症组的主任Ashok Venkitaraman教授发现,甲醛能够降解本来是肿瘤抑制蛋白的BRCA2蛋白,破坏DNA损伤修复机制,使甲醛成为诱发癌症的一个高危因素!对于携带BRCA2基因突变的人来说尤其“凶险”[4]。

Ashok Venkitaraman教授

DNA是我们体内最重要的遗传物质,它的分子结构完整性和稳定性在细胞的存活和发挥正常生理功能上具有重要意义。然而随着细胞的不断分裂,DNA分子工作久了也难免会“开点儿小差”,发生一些自发性损伤,另一方面,外界的理化因素,比如甲醛,作为一种环境毒素,也会造成DNA损伤。

喝酒上脸的同志也需好好看看:英国剑桥科学家阐释甲醛致癌机制——抑制“好”蛋白,还要破坏DNA自我修复

在新的研究中,Venkitaraman教授将人的细胞在甲醛环境中进行体外培养,发现甲醛能够阻止DNA的复制,在细胞中引起DNA链断裂!而一直以来,DNA的损伤都被认为和癌症的发生有着密切关系。那么DNA发生了损伤怎么办?还好我们聪明的人体对此有一套自己的“修复机制”,而正常的BRCA2基因编码的BRCA2蛋白就恰好是一个可以修复DNA损伤、抑制肿瘤发生的蛋白。BRCA2蛋白可以激活另一个和它“搭配”的RAD51蛋白,BRCA2会把RAD51带到DNA链的断裂处,与DNA链结合,对其进行修复[5]。

然而在研究中,Venkitaraman教授发现,甲醛竟然能够降解BRCA2蛋白!在实验中,BRCA2基因未突变的细胞暴露在高浓度300μM的甲醛中5个小时就可以导致BRCA2蛋白被消耗殆尽!而其他的一些也能造成DNA损伤的因素,比如喜树碱、紫外线和电离辐射等等都不会导致BRCA2蛋白的降解。300μM甲醛暴露下,BRCA2蛋白在0-5小时量的变化(电泳条带越来越轻,蛋白量越来越少)


未发生突变的BRCA2基因尚且如此“脆弱”,发生了突变的就更不用说了。基因本来有两个拷贝,当一个拷贝突变后,这个拷贝编码的BRCA2蛋白就不是正常蛋白了,所以正常BRCA2蛋白的量就会随之减少,那么甲醛想要“消耗”掉它们也就更加容易。所以,甲醛会使BRCA2蛋白的量降低到不足以对DNA损伤进行修复,DNA损伤的积累使得染色体的结构和稳定遭到了破坏,癌症也就顺势而生了。而且显然,具有BRCA2突变的细胞对此机制更加“敏感”。

这样看来,甲醛可真是阴险啊!一边损伤DNA,一边又拦住了对损伤的修复,所以这就是在有BRCA2突变的条件下,甲醛致癌的原因了。

对甲醛的研究告一段落后,研究人员又想,除了甲醛外,醛类中的其他常见化合物会不会也有类似效应呢?于是他们接下来又研究了乙醛对BRCA2的影响。乙醛的常见来源是酒精(乙醇),喝了酒之后,酒精会被我们体内的酶分解为乙醛。不幸的是,乙醛并不比它的兄弟甲醛善良!乙醛同样会引起BRCA2蛋白的降解,这也意味着DNA的损伤可能无法被修复。

这时一定有朋友会问,乙醛是可以被乙醛脱氢酶分解,代谢掉的,这样不就没有问题了吗?但是乙醛脱氢酶也是需要其编码基因ALDH2来产生的,而全世界范围内有至少5亿人携带ALDH2基因的突变[6]!他们体内乙醛脱氢酶的量是不足的。

这个突变在东亚血统的人中较为常见,也就是日本、中国和韩国等。乙醛脱氢酶的不足最直接的表现就是喝酒时脸会容易变红,也就是俗话说的“喝酒上脸”。这大概意味着,如果一个人恰好同时携带ALDH2突变和BRCA2突变,那么他喝酒的时候可要小心了!因为他们因喝酒而患癌的可能性要比其他人高得多!

喝酒上脸的同志也需好好看看:英国剑桥科学家阐释甲醛致癌机制——抑制“好”蛋白,还要破坏DNA自我修复

请点击此处输入图片描述 在文章中,Venkitaraman教授表示,他们的研究对公共卫

不过有一点大家应该注意,没有BRCA2突变的人也不可以肆无忌惮。因为研究指出,即使是正常细胞,醛类暴露也会使BRCA2蛋白的量下降,而他们的研究还没有探究出暴露剂量的标准,所以醛类对于正常个体来说,依然是有害的、具有致癌潜力。

参考资料:

[1] http://www.cam.ac.uk/research/news/common-class-of-chemicals-increase-cancer-risk-by-breaking-down-dna-repair-mechanisms

[2] Karoline B. Kuchenbaecker, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA, 2017; 317 (23): 2402 DOI:10.1001/jama.2017.7112

[3] Tai YC, Domchek S, Parmigiani G, Chen S. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. Journal of the National Cancer Institute 2007; 99(23):1811–1814.

[4] Tan S L W, Chadha S, Liu Y, et al. A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability[J]. Cell, 2017, 169(6): 1105-1118. e15.

[5] Jensen, R. B., Carreira, A. & Kowalczykowski, S. C. Nature advance online publication doi:10.1038/nature09399 (2010).

[6] Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals.Yoshida, A., Huang, I.Y., and Ikawa, M.Proc. Natl. Acad. Sci. USA. 1984; 81: 258–261



目前有关喝酒与致癌的相关性研究很多,各种流行病学分析大数据可以信手拈来,以下随便举两个最新的例子,均来自两篇今年刚发表的文章。

喝酒与前列腺癌和肺癌发生率成负相关


Prostate Cancer Prostatic Dis. 2017 Apr 18. doi: 10.1038/pcan.2017.12. [Epub ahead of print]

Total and beverage-specific alcohol intake and the risk of aggressive prostate cancer: a case-control study.

Abstract
BACKGROUND:

Ethanol in alcoholic beverages is a known carcinogen, but its association with aggressive prostate cancer (APC) is uncertain. Recent studies have shown a modest increase in risk of APC associated with heavy alcohol intake while association for beverage types remain inconsistent.

METHODS:

Using a case-control design and self-administered questionnaire, we examined the association between APC (high grade and/or advanced stage) and frequency and quantity of alcohol intake 2 years prior to enrolment. Furthermore, we delineated the relationships for beverage-specific intakes of beer, red wine, white wine and spirits.

RESULTS:

The study included 1282 APC cases and 951 controls. Beer intake frequency of ⩾5 days per week was associated with increased risk compared with no beer intake (odds ratio=1.66, 95% confidence interval: 1.12-2.48) whereas wine was protective at all frequencies of consumption compared with those with no wine intake. For every 10 g per week ethanol intake from beer increase, the odds of advanced PC rose by 3% (OR=1.03, 95% CI: 1.02-1.05). No such increased risk was observed for red or white wine while a marginal dose-response relationship was found for spirits (OR=1.03, 95% CI: 0.99-1.07).

CONCLUSIONS:

Heavy beer and possibly spirits consumption is associated with increased risk while no dose-response relationship was found for red or white wine. Wine drinkers at all frequencies have a decreased risk of APC compared with those who did not drink wine. Prostate Cancer and Prostatic Diseases advance online publication, 18 April 2017; doi:10.1038/pcan.2017.12.


这篇是喝酒与前列腺癌的相关性研究结论:狂饮啤酒(每周5天以上)可提高前列腺癌风险(OR=1.66),而白或红葡萄酒无论喝多少都能防止前列腺癌的发生。至于烈性酒,致癌率仅略有升高(OR=1.03)。

Int J Cancer. 2017 May 1;140(9):1976-1984. doi: 10.1002/ijc.30618. Epub  2017 Feb 27.

Alcohol and lung cancer risk among never smokers: A pooled analysis from the international lung cancer consortium and the SYNERGY study.

Abstract

It is not clear whether alcohol consumption is associated with lung cancer risk. The relationship is likely confounded by smoking, complicating the interpretation of previous studies. We examined the association of alcohol consumption and lung cancer risk in a large pooled international sample, minimizing potential confounding of tobacco consumption by restricting analyses to never smokers. Our study included 22 case-control and cohort studies with a total of 2548 never-smoking lung cancer patients and 9362 never-smoking controls from North America, Europe and Asia within the International Lung Cancer Consortium (ILCCO) and SYNERGY Consortium. Alcohol consumption was categorized into amounts consumed (grams per day) and also modelled as a continuous variable using restricted cubic splines for potential non-linearity. Analyses by histologic sub-type were included. Associations by type of alcohol consumed (wine, beer and liquor) were also investigated. Alcohol consumption was inversely associated with lung cancer risk with evidence most strongly supporting lower risk for light and moderate drinkers relative to non-drinkers (>0-4.9 g per day: OR = 0.80, 95% CI = 0.70-0.90; 5-9.9 g per day: OR = 0.82, 95% CI = 0.69-0.99; 10-19.9 g per day: OR = 0.79, 95% CI = 0.65-0.96). Inverse associations were found for consumption of wine and liquor, but not beer. The results indicate that alcohol consumption is inversely associated with lung cancer risk, particularly among subjects with low to moderate consumption levels, and among wine and liquor drinkers, but not beer drinkers. Although our results should have no relevant bias from the confounding effect of smoking we cannot preclude that confounding by other factors contributed to the observed associations. Confounding in relation to the non-drinker reference category may be of particular importance.

这篇是喝酒与肺癌的相关性研究结论:喝酒与罹患肺癌的风险成负相关,尤其是低度至中度饮用葡萄酒或白酒,但不包括喝啤酒。

由此可知,只要适量饮用葡萄酒及少量饮用白酒,一般是不会提高前列腺癌与肺癌风险的,但喝啤酒却适得其反,大概是因为其酒精含量太低之故。

喝酒与食道癌发生率成正相关

如果读者诸君有空闲也有兴趣,不妨在PubMed里面再搜一下,看看喝酒与其他癌症的相关性如何。若你把时间范围定格在2009年,我预期你一定会搜到下面这篇文章:

PLoS Med. 2009 Mar; 6(3): e1000050.
Published online 2009 Mar 24. doi:  10.1371/journal.pmed.1000050
PMCID: PMC2659709

The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption

Philip J Brooks,*Mary-Anne Enoch, David Goldman, Ting-Kai Li, and  Akira Yokoyama*


Summary Points
  • ALDH2 eficiency resulting from the ALDH2 Lys487 allele contributes to both the alcohol flushing response and an elevated risk of squamous cell esophageal cancer from alcohol consumption.
  • Knowledge of the flushing response is useful clinically, as it allows doctors to identify their ALDH2-deficient patients in a simple, cost-effective, and non-invasive manner.
  • Doctors should counsel their ALDH2-deficient patients to limit alcohol consumption and thereby reduce the risk of developing esophageal cancer.
  • In view of the approximately 540 million ALDH2-deficient individuals in the world, many of whom now live in Western societies, even a small percent reduction in esophageal cancers due to a reduction in alcohol drinking would translate into a substantial number of lives saved.

这篇2009年发表的乙醛脱氢酶缺陷的东亚人(中国人、日本人、韩国人、朝鲜人等)喝酒提高食道癌风险的文章,大概是这些年让大家相信喝酒致癌的始作俑者。这篇文章并非研究论文,而更像是科普性质的综述。当然,它也是基于一系列阳性结果才下的结论。

更有甚者,最近有人根据截至2015年8月31日来自4大数据库(Medline, PubMed, Embase, and Current Contents Connect)的数据,得出了一个确凿结论:喝酒红脸者比不红脸者患食道癌的风险要高(OR=2.54)。

现在的解释是东亚人中喝酒脸红者是乙醛脱氢酶缺陷基因携带者,摄入乙醇后产生的乙醛无法分解成乙酸并进一步分解成二氧化碳和水,而乙醛就是已经确认的致癌剂。

可是,为什么喝酒只导致食道癌而不诱发其他癌症呢?既然乙醛可以随血液在全身循环,它也应该诱发其他癌症吧?!

乙醛减少肿瘤抑制蛋白并降低DNA损伤修复效率

现在暂且把上面这个问题放在这儿,先看看为什么乙醛能致癌吧。今年6月1日Cell发表的一篇最新论文比较圆满地回答了这个问题。

Cell. 2017 Jun 1;169(6):1105-1118.e15. doi: 10.1016/j.cell.2017.05.010.
A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability.Abstract

Mutations truncating a single copy of the tumor suppressor, BRCA2, cause cancer susceptibility. In cells bearing such heterozygous mutations, we find that a cellular metabolite and ubiquitous environmental toxin, formaldehyde, stalls and destabilizes DNA replication forks, engendering structural chromosomal aberrations. Formaldehyde selectively depletes BRCA2 via proteasomal degradation, a mechanism of toxicity that affects very few additional cellular proteins. Heterozygous BRCA2 truncations, by lowering pre-existing BRCA2 expression, sensitize to BRCA2 haploinsufficiency induced by transient exposure to natural concentrations of formaldehyde. Acetaldehyde, an alcohol catabolite detoxified by ALDH2, precipitates similar effects. Ribonuclease H1 ameliorates replication fork instability and chromosomal aberrations provoked by aldehyde-induced BRCA2 haploinsufficiency, suggesting that BRCA2 inactivation triggers spontaneous mutagenesis during DNA replication via aberrant RNA-DNA hybrids (R-loops). These findings suggest a model wherein carcinogenesis in BRCA2 mutation carriers can be incited by compounds found pervasively in the environment and generated endogenously in certain tissues with implications for public health.

这篇论文的重点是研究甲醛对DNA损伤修复蛋白(肿瘤抑制蛋白)BRCA2的影响,但也顺带做了乙醛作用于BRCA2的研究。结果表明,甲醛和乙醛都能通过蛋白酶体降解作用使BCRA2减少甚至丧失,结果导致DNA损伤修复效率大为降低,于是基因突变率提高,癌症发生率也随之提高。

这里点出了一个关键因素,那就是BRCA2的有无及其活性。如果你不幸是BRCA2缺陷者,那么你绝对不能接触甲醛和乙醛,否则极易致癌。由此推论,家族性BRCA1/BRCA2基因缺陷者应该滴酒不沾,因为酒类不仅含乙醇也会掺杂甲醇,不然就很容易诱发乳腺癌和子宫癌。

BRCA减少还有其他原因——启动子甲基化下调表达

现在再回到前面的问题,喝酒脸红的东亚人是乙醇脱氢酶基因缺陷者,而那些患食道癌的乙醇脱氢酶基因缺陷者难道也是BRCA2基因缺陷者?如果真是这样,难怪有人一本正经地开着玩笑说:得不得癌全靠运气!

不过,虽然家族遗传性BRCA2基因缺陷携带者非常罕见,但这并不等于说BRCA2基因表达不会出现异常,也不意味着BRCA2蛋白不会发生功能失活。比如,有人就在乳腺癌患者中报道过BRCA2基因启动子甲基化导致的表达下调。


Asian Pac J Cancer Prev. 2015;16(18):8599-604.
Methylation Status and Expression of BRCA2 in Epithelial Ovarian Cancers in Indonesia.
Abstract

Ovarian cancer is the main cause of mortality in gynecological malignancy and extensive studies have been conducted to study the underlying molecular mechanisms. The BRCA2 gene is known to be an important tumor suppressor in ovarian cancer, thereby BRCA2 alterations may lead to cancer progression. However, the BRCA2 gene is rarely mutated, and loss of function is suspected to be mediated by epigenetic regulation. In this study we investigated the methylation status and gene expression of BRCA2 in ovarian cancer patients. Ovarian cancer pateints (n=69) were recruited and monitored for 54 months in this prospective cohort study. Clinical specimens were used to study the in situ expression of aberrant BRCA2 proteins and the methylation status of BRCA2. These parameters were then compared with clinical parameters and overall survival rate. We found that BRCA2 methylation was found in the majority of cases (98.7%). However, the methylation status was not associated with protein level expression of BRCA2 (49.3%). Therefore in addition to DNA methylation, other epigenetic mechanisms may regulate BRCA2 expresison. Our findings may become evidence of BRCA2 inactivation mechanism through DNA methylation in the Indonesian population. More importantly, from multivariate analysis, BRCA2 expression was correlated with better overall survival (HR 0.32; p=0.05). High percentage of BRCA2 methylation and correlation of BRCA2 expression with overall survival in epithelial ovarian cancer cases may lead to development of treatment modalities specifically to target methylation of BRCA genes.

炎症通过一氧化氮下调BRCA1表达

不久前,有人报道炎症条件下一氧化氮通过表观遗传调节导致BRCA1表达下调的研究结果,证明BRCA1水平受环境因素影响较大。

Redox Biol. 2015 Aug;5:414. doi: 10.1016/j.redox.2015.09.013. Epub  2015 Dec 30.
Nitric Oxide: Genomic Instability And Synthetic Lethality.Abstract

Regardless of etiology, inflammatory conditions are characterized by overexpression of inducible nitric oxide synthase (iNOS) and overproduction of nitric oxide and reactive nitrogen species (NO/RNS) in epithelial and inflammatory cells at the site of carcinogenesis. NO/RNS produced in inflamed tissues can contribute to the process of carcinogenesis by different mechanisms. One of these mechanisms is NO-dependent stimulation of genomic instability by inhibiting of Breast Cancer type 1 Susceptibility protein (BRCA1) expression. Block of BRCA1 expression shifts DNA double-strand breaks (DSB) repair from error-free high-fidelity homologous recombination repair (HRR) to error-prone nonhomologous end joining (NHEJ). BRCA1 epigenetically block miRNA-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miRNA-155 promoter. The miRNA-155 is responsible for post-translational silencing of essential members of mismatch repair (MMR) core: MSH2, MSH6, and MLH1 proteins. They epigenetic inactivation induces DNA microsatellite instability (MSI). Recently, we demonstrated NO-dependent downregulation of MMR core proteins (MSH2, MSH6, and MLH1) through the ↓BRCA1/↑miRNA-155 signaling pathway. Hence, another NO-dependent mechanism of genomic instability is downregulation of MMR core proteins and stimulation of the DNA MSI. Loss or inhibition of Poly(ADP-ribose) polymerase 1 (PARP1) activity results in accumulation of DNA single-strand breaks, which are subsequently converted to DSB by the transcription machinery. In BRCA-positive cells, DSB are repaired by HRR, but they cannot be properly repaired in BRCA1-deficient cells, leading to genomic instability, chromosomal rearrangements, and cell death. Our data demonstrated that combination of NO-donors with PARP inhibitors significantly sensitized the BRCA1-positive cancer cells to DNA-damaging agents.

根据以上结果,我们不妨这样假定,如果某位喝酒脸红的人体内正好有炎症,那么ta的BRCA1/BRCA2表达就会下调。当ta豪饮且经常饮酒后,口腔接触高浓度乙醛可大规模破坏ta的DNA,而BRCA1/BRCA2又因含量不足,便不能有效修复DNA损伤,结果不幸患上了食道癌。

喝酒致癌的结论也许是这么得出来的

如果这个病例被纳入喝酒与食道癌相关性的流行病学分析,那么必然得出喝酒提高食道癌风险的结论,可是却没有患者体内炎症水平的数据,更不会有BRCA1/BRCA2表达及功能的数据。这样分析起来无意中就给将来的研究提供了一条思路:无论是流行病学分析,还是分子病理分析,探讨喝酒与癌症的关系都应该纳入炎症指标,尤其是BRCA1/BRCA2等的表达及功能数据,从而确认喝酒是否引起BRCA1/BRCA2失活及基因突变。

一个人会不会患癌,接触致癌剂是一个大的风险因素,而自身的DNA修复系统缺陷是一个更大的风险因素。这就是为什么同样受到致癌因素攻击,有的人容易得癌症,有的人却不得癌症的道理,正可谓“正可压邪”,“正气存内,邪不可干”。

不过,我们的研究发现,用15%乙醇给小鼠灌胃,可以消除肠道感染引起的关节红肿,表明乙醇的抗炎作用明显。生活中的经验也告诉我们,我国民间喝酒抗风湿的习俗也表明喝酒具有消炎止痛的功效。因此,喝酒致癌的结论还缺乏足够的科学依据,不然为什么除食道癌外喝酒并未导致癌症风险提高,但在得出确切结论之前,还是建议大家尤其是喝酒脸红者不要酗酒,而且尽量不要喝高度酒。




http://blog.sciencenet.cn/blog-281238-1063022.html

上一篇:SCI,投或不投,都是纠结
下一篇:青蒿素减肥,居然上不了CNS子刊的版面?
收藏 分享 举报

6 李颖业 吴炬 侯沉 黄旭 bridgeneer trueego

该博文允许注册用户评论 请点击登录 评论 (6 个评论)

数据加载中...

Archiver|手机版|小黑屋|科学网 ( 京ICP备14006957 )

GMT+8, 2017-9-20 04:43

Powered by ScienceNet.cn

Copyright © 2007-2017 中国科学报社

返回顶部