关于坏血病的遗传病因学

On the Genetic Etiology of Scurvy

作者: Irwin Stone

来源:WWW.CFORYOURSELF.COM

翻译:蓝 山

 

众所周知，人缺乏抗坏血酸（即维生素C）会发生坏血病并注定会在几个月内死亡。在1930年代的早期，抗坏血酸被认定为食物中发挥预防这种致死疾病的主要成分。在发现抗坏血酸之前的20年，这种抗坏血酸因子被认为是食物中尚不清楚的称为维生素C的微量物质，而此前的数百年，事实上已经知道蔬菜、肉类和鱼类中的某种物质可以预防或治疗坏血病。　

坏血病是一种古老的疾病，Hippocrates (Hirsch, 1885)和古埃及人都有提到这种病(Ebbell, 1938; Bourne, 1944)。在漫长的人类史前或历史，坏血病比任何单一因素引致更多的死亡、痛苦和改变历史进程。自人类和其原始祖先离开热带或热带地区，迁移到温带地区，他们就遇到麻烦，当人类学会了煮食他们的肉和鱼，因而减少了不稳定的抗坏血酸的含量，更加重了他们的坏血病症状。每年在冬季末段或春季，已被一年一度的坏血病削弱的全体人口，再被继发性入侵的病毒感染及其他疾病所杀死。相当庆幸的是，现代人用于生存所需的抗坏血酸量是很少的。

基本上，坏血病的原因是人类的肝脏不能合成抗坏血酸。这种合成在几乎所有生物中是普遍的(Chatterjee et al., 1961).。大多数哺乳动物正常情况下不会得坏血病，不管其饮食中抗坏血酸少到何种程度。他们连续合成并稳定地提供抗坏血酸这种重要的生理物质。直到1907年，坏血病一直被认为纯粹是一种人类疾病，因为看来没有任何其他动物受这种病的威胁，在那一年，天竺鼠（guinea pig））被发现同样会得坏血病(Holst and Frich, 1907)。

哺乳动物肝脏巧妙有序地利用葡萄糖合成抗坏血酸，每个步骤分别由特异性酶控制(Grollman and Lehninger, 1957; Burns, 1959)。这种完整的酶系统在除人类、部分猴子，天竺鼠和一种印度食果蝙蝠Pteropus medius(Chatterjee et al., 1961)外的所有哺乳动物中均存在。这几种例外的动物是唯一会得坏血病的哺乳动物。如果饮食中缺乏抗坏血酸，坏血病在天竺鼠是快速致死性疾病，它们常在二到三个月内死亡。

人类肝脏缺乏转化葡萄糖为抗坏血酸的系列酶中的最后一种酶。这种酶—古洛糖酸内酯氧化酶（GLO）的缺乏完全阻断了这种合成，虽然人肝脏含有其他几种酶(Chatterjee et al., 1961)。这种酶的缺乏是由于合成这种酶所需的基因的遗传性缺乏或缺陷。因此，坏血病是一种典型的遗传性疾病。在病原学上，和其他遗传性疾病如苯丙酮酸尿（PKU），半乳糖血症，尿黑酸尿和其他遗传性代谢疾病相类似。这些遗传性疾病都是由某种基因的遗传性缺陷而产生。特定基因的缺乏或无活性导致特别的病理代谢综合征。

虽然涉及人类抗坏血酸合成的遗传缺陷看来在生化遗传学方面已清楚定义，抗坏血酸仍然被医学科学看成是维生素C。我一直未能发现任何一些相关报道，就是试图改变坏血病目前的定义：作为一种营养不良或维生素缺乏症。而应定义为一种遗传性疾病以符合其本质。因为目前缺乏对这种遗传性疾病的认识。我建议把这种遗传性的坏血病综合征命名它为：抗坏血酸缺乏症（Hypoascorbemia）。以对少数几种呈普遍性的、异常低的、抗坏血酸血症的哺乳动物的尊重。而显性坏血病则可被考虑为是这种状况的终极后遗症。

这种遗传疾病，抗坏血酸缺乏症（Hypoascorbemia），在病原学上和其他已知的遗传病如苯丙酮酸尿（PKU）及其它遗传病相似。但其发病率显著不同，其它遗传病在人群中相对少见，而抗坏血酸缺乏症（Hypoascorbemi）看来影响全部人口。因而，现在这里有一种严重的，且目前为止尚未被认识的，累及全人类的遗传疾病，这种遗传疾病看来在整个人类历史上仅作过一点或略多一点的“纠正”。这种遗传病的全面纠正的缺乏可能是影响死亡率或患病率，衰老过程及人类寿命的重要因素之一。术语“纠正”意思是向个体供给其肝脏本来每天合成抗坏血酸的量，假设没有发生遗传突变的话。从仅有不多资料计算得出结论，推测这些“纠正”所需的量是维生素C理论推荐量的许多倍。

合成这种活性酶—古洛糖酸内酯氧化酶（GLO）的基因的丢失可能是人的灵长类祖先约在5千万年前发生了条件性基因突变(Gluecksohn-Waelsch, 1963)。如果作者的建议—检查灵长目各成员的这种酶系统获得认同和实施的话，可能更好地确定突变发生的时间(Stone, 1965)。这种不利的基因突变并没有淘汰这种生物的原因是因为其食物含少量的抗坏血酸，足以保证其生存之故。

人的一生都受累于这种遗传突变的不良影响，并且完全依赖于食物提供少量的这种其肝脏不能合成的重要生理物质。他从不能获得他自己的肝脏本应合成的数量的抗坏血酸。如果我以这种功能完全正常的哺乳动物—鼠，所合成的抗坏血酸的量计算的话，不受压力的鼠每天每公斤合成70毫克的抗坏血酸(Salomon and Stubbs, 1961)，而应激情况下，增加到每公斤体重215毫克(Conney et al., 1961)。这相当于体重70公斤的人每天合成4.9~15克的抗坏血酸。由于食物中不稳定的微小数量，实际上，身体根本不能消化含有相当于上述数量的抗坏血酸的重量和体积的食物。

这不是第一次质疑食物中的抗坏血酸含量并不足以产生最优水平的抗坏血酸。在1949，Bourne指出，人类的最近亲—猿猴，其主食是植物，他估计一个猿猴在其栖息地每天消化4.5克的抗坏血酸。据推测猿猴和人一样易得坏血病。Bourne,亦提议：目前推荐的维生素C日摄入量和最合理的量相差很远，也许，应以克代替毫克来计算。他说，“我们的血液和组织应达到维生素C饱和程度，并从尿液和汗液排泄，我们或许会发现这种高饱和浓度的抗坏血酸持续一段时间将会有明显和无可争议的抗感染作用。”

在上述依据鼠的数据而作的抗坏血酸的合成的估计中，考虑到人和鼠的体重的具大差异，这可以影响所作的推论。然而，这是目前仅得的数据，因而，更突出了需要对长久忽视的哺乳动物合成抗坏血酸的量化指标作更多的研究。如果这些数据有效的话，人在其一生中一直生活在极低水平的抗坏血酸中。这自然产生了如下问题：在这么长的时间里，人的生理发生了什么事情以及，如果供给他其他哺乳动物合成抗坏血酸的量的话，他会受益吗？这亦说明了人类生理机能的粗壮。因其一直适应远低于其他哺乳动物的抗坏血酸水平。

史前时期，坏血病一直陪伴我们，但遗传性疾病或先天性代谢缺陷的概念在1908年后才出现(Garrod, 1908)。多个世纪以来，坏血病和新鲜食物有密切的关系，因而，医学界很久以来一直认为坏血病是一种营养失调疾病，19世纪末营养科学和20世纪初维生素理论的发展进一步巩固了这些错误的营养概念。当这些概念流行的时候，这些假设看来是仅得的清晰且合乎逻辑的解释。从现代知识来看，然而，再没有任何理由继续相信这种不堪一击的坏血病病原学的维生素C理论。这种维生素C理论的唯一合理性是其作为历史上的一种理论，如果坏血病是一种在过去10年内才被发现的一种疾病，毫无疑问，它会定位于它合适的位置—一种遗传性疾病。

坏血病是一种遗传性疾病而并非仅是一种营养失调这样一个事实的含义远大于一个迷人的假设或仅仅是个语言学上的事情。坏血病的遗传学的认识以及需要向人体提供其肝脏本应合成的抗坏血酸的数量，在医学和治疗上，将会有极其重要的结果。当前，医学界在医学和临床治疗上，基本不把抗坏血酸作为一种实际上涉及生物所有的生理过程而且相当重要的，已消失的内源性生化物质，而仅认为它是一种只需要微量就可以预防或治疗坏血病的特殊外源性营养素。

因为令人迷惑和过去30年众多矛盾的临床试验报告，现在抗坏血酸在坏血病以外的其他疾病的临床应用被排斥，对这些令人困惑、矛盾的临床报告，运用遗传学概念，将会从混乱中找到正确判断的尺度。　大多数临床研究报告者都受训于认为抗坏血酸是一种维生素C，因而，他们仅用毫克算的用量治疗这些疾病，以为他们是坏血病。少数研究者偶然用以克计算的抗坏血酸，他们就能取得满意效果甚至于是惊人的成功。　他们无意地使用了接近哺乳动物每天合成抗坏血酸的量，因而纠正了病人的抗坏血酸缺乏症。在此状态下，病人维持最佳的生理反应并能获得抗坏血酸独特的治疗效果。过去的30年，我们一直在对坏血病以外的其他疾病的抗坏血酸的临床应用作全面而批评性总结(Stone, 尚在准备之中)。到目前为止的研究结果，支持上述理论。

这个遗传概念为临床上大剂量使用抗坏血酸，单独或配合其他治疗提供了新的合理性依据，并为在发明抗坏血酸后30年来未涉及的领域作临床试验开辟了新的前景，包括对人非常重要的如感染性疾病、胶原疾病，心血管疾病、癌症和衰老过程等的研究。希望，这篇文章的出版会促进这些项目的进一步思考，加速开展相应的临床研究。

小结

坏血病—现在认为是一种由于食物中缺乏微量营养素维生素C的饮食失调，实际上是一种典型的遗传疾病的最后结果。这种遗传性综合症已被命名为抗坏血酸缺乏症（Hypoascorbemia）。它的基本原因是控制合成抗坏血酸的酶_古洛糖酸内酯氧化酶（GLO）的遗传性缺少或缺陷 。这是一种哺乳动物的肝酶，在转化葡萄糖为抗坏血酸的一系列酶当中的最后一种。人是少数几种缺少这种基因的哺乳动物之一。基因缺陷发生在进化过程中的一次条件性基因突变。在坏血病的病原学上，以遗传概念代替现在的维生素理论，对正常生理情况下以及在坏血病以外的治疗中大量使用抗坏血酸提供新的视点。

　

On the Genetic Etiology of Scurvy

Irwin Stone

It is well known that humans deprived of ascorbic acid will develop scurvy and death will ensue in a few months. In the early nineteen-thirties, ascorbic acid was identified as the antiscorbutic principle in foodstuffs that provided the prophylaxis against this fatal disease. In the two decades prior to the discovery of ascorbic acid, the antiscorbutic factor was considered as some unknown trace substance in foods called «vitamin C». For hundreds of years before this, it was known empirically that something in fresh vegetation, meat or fish would prevent or cure scurvy.

Scurvy is a very ancient disease; it was mentioned by Hippocrates (Hirsch, 1885) and the Egyptians had several hieroglyphs for writing about the disease (Ebbell, 1938; Bourne, 1944). In the long period of human prehistory and history, scurvy has caused more deaths, created more human misery and has altered the course of history more than any other single cause. As soon as Man or his primitive ancestors left their original tropical or semi-tropical environment and moved to the temperate climes where fresh vegetation was no longer available the year round, they were in trouble. When Man learned to cook his meat and fish, thus reducing its unstable ascorbic acid content, their scorbutic difficulties were further compounded. Each year in the late winter and spring, the whole population, weakened by the annually recurring ravages of scurvy, was decimated by the secondary invading virulent infections and other diseases. It is indeed fortunate for us, the present surviving human population, that the requirements for ascorbic acid for mere survival are low.

Basically, the cause of scurvy is the inability of the human liver to synthesize ascorbic acid. This synthesis is common to nearly all forms of life and is accomplished in the liver of most mammals (Chatterjee et al., 1961). These mammals cannot normally contract scurvy no matter how little ascorbic acid or vitamin C is in their diet. They continually manufacture a steady supply of this important physiological substance in fairly large amounts. Up to 1907 scurvy was considered primarily a human disease because no other animal appeared susceptible to it. In that year it was found that guinea pigs could be made scorbutic (Holst and Frölich, 1907).

The mammalian liver produces ascorbic acid from glucose by a step-wise synthesis, each step being controlled by a separate specific enzyme (Grollman and Lehninger, 1957; Burns, 1959). This complete enzyme system is present in all mammals except Man, some monkeys, guinea pigs and an Indian fruit-eating bat, Pteropus medius (Chatterjee et al., 1961). These few exceptions are the only mammals that will develop scurvy if deprived of ascorbic acid in their diet. The disease is rapidly fatal in guinea pigs; they succumb in about two or three weeks.

Man’s liver lacks the last enzyme in the series needed to convert glucose to ascorbic acid. The lack of this one enzyme, L-gulonolactone oxidase, completely blocks the synthesis even though the human liver contains the other intermediate enzymes in the series (Chatterjee et al., 1961). The absence of this enzyme is caused by the hereditary lack or defect in the gene required for its synthesis. Thus the syndrome of scurvy is a typical genetic disease similar in etiology to other recognized genetic diseases such as phenylketonuria (PKU), galactosemia, alkaptonuria and the many others in this continually growing list of genetic metabolic anomalies. These genetic diseases are all caused by an inherited defect in the gene which controls the synthesis of the particular enzyme whose absence or lack of activity causes the specific pathologic metabolic syndrome.

While the genetic defect involved in human ascorbic acid synthesis seems to be clearly defined in biochemical genetics, ascorbic acid is still regarded by Medicine as «vitamin C». I have been unable to find any reference which attempts to change scurvy’s present classification as a nutritional disorder or avitaminosis and assign it to its true position as a genetic disease. Because of this current lack of recognition of its genetic status I propose the name,Hypoascorbemia, for the genetic scorbutic syndrome, in deference to the generally abnormally low blood levels of ascorbic acid which can exist in the few mammals with this defective gene. Frank scurvy may then be considered as the extreme sequela of hypoascorbemia.

The genetic disease, hypoascorbemia, is of similar etiology to recognized genetic diseases like PKU and the many others with one notable difference in incidence. The other genetic anomalies are of comparatively low occurrence among the human population, while hypoascorbemia seems to afflict all of Mankind. Thus we have here a serious and, up to now, unrecognized genetic disease of apparent universal incidence among humans, which appears to have been only marginally or sub-marginally “corrected” throughout the whole history of Man. The lack of “full correction” of this genetic metabolic anomaly may be a very important factor in the incidence and morbidity of diseases, in the aging process and in the extent of the human life span. The term “correction” means supplying to the individual, ascorbic acid in amounts the liver would be synthesizing were this genetic defect not present. These “correcting” amounts calculated from the scant data available are indicated to be many times those suggested, as adequate, by the vitamin C theory.

The loss of the gene for the synthesis of the active enzyme, L-gulonolactone oxidase, probably took place in some remote Primate ancestor of Man by a conditional lethal mutation (Gluecksohn-Waelsch, 1963), possibly some fifty million years ago. It may be possible to better pinpoint where in Time this mutation occurred if the author’s suggestion for examining various members of the Primate order for this enzyme system, is followed (Stone, 1965). The reason that this unfavorable mutation did not eradicate the mutated animals was the presence of small amounts of ascorbic acid in their available foodstuffs, adequate to insure their survival.

Man has suffered from this genetic defect throughout his entire existence and has been absolutely dependent upon his food supply to provide him with marginal amounts of this important physiological substance that his liver fails to synthesize. He was never able to obtain in his foods amounts of ascorbic acid that his liver should have been producing, if we judge this by the amounts synthesized by another mammal, the rat, endowed with the complete enzyme system. The unstressed normal rat synthesizes ascorbic acid at the rate of 70 mg per Kg. of body weight per day (Salomon and Stubbs, 1961) and the stressed rat increases this to 215 mg. per Kg. per day (Conney et al., 1961). This is equivalent to the production of 4.9 to 15.0 gm. of ascorbic acid per day calculated to the 70 Kg. weight of an adult human. Because of the meager amounts of the unstable ascorbic acid in foods, it is just physically impossible to ingest enough weight of food material to supply these gram quantities of ascorbic acid.

This is not the first time that the possible inadequacy of foods for supplying optimal levels of ascorbic acid has been questioned. Bourne, in 1949, noted that for our closest mammalian relatives, the great apes, their chief foodstuff is vegetation. He estimated that a gorilla in its natural habitat consumes about 4.5 gm. of ascorbic acid per day. The gorilla presumably also suffers from the same genetic defect as Man. Bourne also suggested that the currently recommended mg. per day intakes may be wide of the optimal amount and perhaps should be measured in gm. per day instead. He stated “Perhaps it is normal for our blood and tissues always to be saturated with the vitamin and for large quantities to be flushing constantly through our urinary system and excreted in our sweat. We may find that continuous doses of vitamin C at this (high) level over a considerable period of time may have pronounced and unequivocal anti-infective action”.

In the above estimate of ascorbic acid production based on rat data, it is realized that there is a large disparity in body size of rats and humans which may affect the extrapolation. However, this is the only data presently available and sharply points up the need for much more work in the long-neglected area of the quantitative synthesis of ascorbic acid by the larger mammals. If these high figures are valid, then Man throughout his entire existence has been getting along on extremely low quantities of ascorbic acid in contrast to the other mammals. It certainly raises questions as to what has happened to Man’s physiology during this long period of time and if he would benefit by being supplied with ascorbic acid in amounts comparable to that produced by other mammals. It also bespeaks well of the ruggedness of human physiology to have been able to adapt to ascorbic acid levels so much below that of the other mammals.

Scurvy has been with us since prehistory but the concept of genetic diseases or the inborn errors of metabolism dates only from 1908 (Garrod, 1908). Over the centuries, there has been a close association of scurvy with the lack of fresh foods, thus the medical profession has long regarded the scorbutic syndrome merely as a nutritional disturbance. The development of the nutritional sciences in the latter part of the nineteenth century and of the vitamin theory in the early decades of the twentieth century further strengthened the hold of these erroneous nutritional concepts. When they were postulated, these hypotheses seemed to be a clear and logical explanation of the facts available. In the light of our present knowledge, however, there is no reason for continuing the untenable vitamin C theory of the etiology of scurvy whose only justification now is a historical one. If scurvy were a disease only discovered in the last decade there is no doubt that it would have been assigned its rightful place as a genetic disease.

The implications of the fact that the scorbutic syndrome is a genetic metabolic anomaly rather than a nutritional disturbance is much more than a fascinating hypothesis or a mere matter of semantics. The recognition of the genetic etiology of scurvy and the need for supplying ascorbic acid at levels the human liver should be synthesizing would have extremely important consequences in medicine and therapy. At present, Medicine generally regards ascorbic acid not as an important missing endogenous biochemical product that is involved in practically every physiological process of the living organism but instead as vitamin C — merely a specific exogenous nutrient which in trace amounts will prevent or cure scurvy.

The whole field of the therapeutic use of ascorbic acid in many diseases other than scurvy is now dismissed because of the confusing and conflicting clinical results in the thousands of papers published in the last thirty years. The application of these genetic concepts to this vast medical literature brings a measure of order out of the chaos. Most of the clinical investigators reporting in these papers were trained to think of ascorbic acid as “vitamin C” and hence they treated these other clinical entities as if they were scurvy, giving only vitamin-like dosages of mg. per day and they reported poor or indifferent clinical results. A few other workers fortuitously using ascorbic acid in doses of many gm. per day were the ones who were able to report clinical success and even dramatic cures. Unknowingly, these investigators had used ascorbic acid closer to the range occurring in mammalian synthesis and thereby had overcome the hypoascorbemia in their patients. In this manner they maintained physiological responses at optimal levels and were able to take advantage of many of ascorbic acid’s unique therapeutic properties. We have been engaged in the preparation of a comprehensive and critical review of the clinical work on the therapeutic use of ascorbic acid in diseases other than scurvy during the past three decades (Stone, in preparation). The results of this survey, to date, support the above thesis.

This genetic concept provides a new rationale for the therapeutic use of high levels of ascorbic acid either alone or in combination with other medicaments, and opens vistas of clinical testing in many areas that have lain fallow in the three decades since the discovery of ascorbic acid. These include areas of such fundamental importance to Man as the infectious diseases, the collagen diseases, cardiovascular conditions, cancer and the aging process. It is hoped that the publication of this paper will stimulate further thinking on this subject and give impetus toward initiating the required clinical research.

Summary

Scurvy, now regarded as a nutritional disorder due to the lack of the trace food constituent, vitamin C, is shown to be the end result of a typical genetic disease. This genetic disease syndrome has been named Hypoascorbemia. Its primary cause is the hereditary lack of — or defect in — the gene controlling the synthesis of the enzyme, L-gulonolactone oxidase. This is a mammalian liver enzyme, the last one in the series for converting glucose into ascorbic acid. Man is one of the few mammals that lacks this enzyme and hence is unable to synthesize his own ascorbic acid. The gene defect occurred during the course of evolution by a conditional lethal mutation. The replacement of the present vitamin C theory regarding the etiology of scurvy by this genetic concept gives important new viewpoints to the quantitative aspects of ascorbic acid in human physiology and also provides new rationales for the use of high levels of ascorbic acid in normal physiology and in the therapy of clinical entities other than scurvy.

　

　

参考书目 REFERENCES

　

Author’s address: Dr. Irwin Stone, 208 Winchester Ave., Staten Island, N. Y. 10312, U.S.A.

　

From Acta Geneticae Medicae et Gemellologiae, 1966, Volume 15, pp. 345-350

http://seanet.com/~alexs/ascorbate/196x/stone-i-acta_genet_med_et_gemell-1966-v15-p345.htm