(The Natural History of Ascorbic Acid in the Evolution of the Mammals and Primates and Its Significance for Present Day Man)
作者: Irwin Stone
IRWIN STONE 是受训的化学工程师，职业的生物化学家，业余的古病理学家。他在1934年开始研究抗坏血酸，获得美国第一项把抗坏血酸作为食品抗氧化剂的专利。这项工艺在全世界范围内的应用是显性坏血病在发达国家基本上消失的一个因素。在1965~1967年，他发表了一系列论文，描述遗传性的肝酶疾病，HPPOASCORBEMIA，以及它在医学上的意义。这种新的遗传学方法为正分子医学大剂量应用抗坏血酸提供了理论依据。他现在是MEGASCORBIC RESEARCH INC的研究主任。
1. The Reversal Oxidation-Reduction
图一 可逆的氧化-还原系统， 抗坏血酸（左）-脱氢抗坏血酸（右）
目前所有已检查过的每一种原始非脊椎动物和低等生物都显示抗坏血酸的存在。 Bourne and Allen;2 Bourne.3 在几乎所有已检查过的脊椎动物，抗坏血酸制造都在正常状态。那些不能合成抗坏血酸的少数品种，是在它们的酶制造系统，患有一种遗传性缺陷。因此必须从它们的食物中获得抗坏血酸或者就会死于坏血病。
表一，依据从检查现在的不同动物获得的数据，标出脊椎动物从鱼到灵长类的进化历程中，抗坏血酸和其酶系统的位置。Chatterjee et al.1 Roy and Guha5; Chaudhuri and Chatterjee.6
现在的鸟类，它们的祖先看来和哺乳动物的祖先在同一时期出现，仍然显示出这种肾-肝转移。 Chaudhuri and Chatterjee.6 现在鸟类的更古的目，如鸭、鸽和鹰，在肾脏合成它们的抗坏血酸，而更近的的目如perching和鸣鸟，Passeriformes，一些同时在肾和肝，一些在肝脏合成其抗坏血酸。一些，如人类，完全不能合成抗坏血酸。
直至1907年，坏血病仍然被认为完全是一种人类疾病，因为没有已知的其他动物容易患上它。在1907年，Holst and Frohlich7, 在挪威鱼船队上研究脚气病（beriberi），需要一种小的哺乳动物（天竺鼠）替代当时作为实验动物的鸽子。他们喂给天竺鼠实验用的饮食，一种导致鸽子产生脚气病的饮食。令他们惊奇的是，产生的是坏血病。后来，发现实验性猴子亦容易患上坏血病。人，天竺鼠和一些猴子，不能合成他们的自己的抗坏血酸。
在1912年，维生素假说问世 (Funk8)。 假说的部分叙述，坏血病是由一种尚不清楚（存在于饮食中的，称为“维生素C ”）的水溶性物质的缺乏而引起的一种缺乏病。20年后，在1932年，(Svirbely and Szent-Gyorgyi，匈牙利科学家，发现和分离出维生素C， 因此获诺贝尔奖 ), 得知抗坏血酸和维生素C是同一样物质。 Burns10 在1959年发现容易患坏血病的少数哺乳动物的基本生化损伤，是由于他们的肝脏不能制造这种活性酶—L-古洛糖酸内酯氧化酶。这种酶涉及哺乳动物转化血中的葡萄糖为抗坏血酸。这种合成，涉及四种酶，在图2展示，人类的肝脏有前面三种酶，但他缺乏第四种，这样完全阻断了其肝脏抗坏血酸的制造。
这个建议被采纳了，哈佛大学 在1966年发表实验报告(Elliott et al.11)，而Yerkes 灵长类动物研究中心在1969年发表实验报告(Nakajima et al.12)，他们的实验结果显示，所有已检查的猴子，亚目Prosimii，活性酶L-古洛糖酸内酯氧化酶，存在于他们的肝脏。而亚目类人猿的成员，则是无活性的。虽然数据不完全代表灵长类目的全部成员，现在的样品提示，这些灵长类动物容易患坏血病和不容易患坏血病的分界线，可能就是在两个主要的亚目，Prosimii和 类人猿。
这种分界线在图三显示，由Simons.13创立的一份灵长类目的化石记录表，右边第二栏，是现在的灵长类族的目录。最右边的一栏，标有“Liver GLO”，包含为查证活性酶L-GLO的存在，而最近对灵长类动物的肝脏检查的结果。在所有已检查的灵长类动物，那些在亚目类人猿的六属，在其肝脏缺少这种酶，而那些在Prosimii 4属的灵长类，其肝脏有这种酶，可以合成自己的抗坏血酸。虽然应检查其他更多的Prosimii成员如Lemuridae, Tarsiidae and Daubentoniidae，现在的提示是，Prosimii 和 类人猿的界限，不但在形态上，而且，也在这个重要的生理参数上。
3. Chart of the Fossil Record of the Primates with the Occurrence of
Active L-Gulonolactone Oxidase
图三： 标有活体灵长类的肝脏的L-古洛糖酸内酯氧化酶 的出现时间的灵长类化石记录表（化石记录来自Simons13）
如果我们顺着箭头，推测这种分界线回到表上所列的时间，然后，我们到达一点，界乎 白恶纪的后期Paleocene 后期，就在这里，这种摧毁了控制合成酶蛋白，L-古洛糖酸内酯氧化酶的基因的突变，看来已经发生。这出现在灵长类出现不久，大约5800~6300万年前，在 spurred circle附近。在其后代进化为其亚目类人猿的灵长类发生了这种基因突变。
可能不只是巧合，在白恶纪的后期的附近，当种灵长类的突变发生时，有一个短暂的间隔，此时很多其他生物正经历严重的分化减弱或变得消失，包括许多非脊椎动物和著名的恐龙，突然从化石记录中消失。Russell and Tucker14 在1971年提议，一个邻近的超新星大爆炸，由于宇宙射线的释放，以及大气层吸收大量的宇宙射线如gamma 射线和X 射线，可能产生的气候变化是如此剧烈，以致引起包括恐龙在内的许多动物灭绝。如果这样一个天文事件发生，过后，随便吸引其中的一些高能辐射，可能在导致这种灵长类动物控制合成酶蛋白—L-古洛糖酸内酯氧化酶的基因发生突变中发挥作用，导致出现一种无活性的酶。
由于这些进化研究的结果，Stone19 在1966年指出，由于这种有缺陷的基因，产生一种无活性的酶，现代人正经受一种哺乳动物的先天性碳水化合物代谢错误，它已被命名为抗坏血酸缺乏症(HYPOASCORBEMIA)。坏血病，实际上是这种遗传性肝酶疾病的后遗症，它使人必须从外部来源获得抗坏血酸。Stone.20 60年来，抗坏血酸一直被认为是一种“维生素“，而实际上它是一种肝脏代谢物，对大多数有完整的基因，以制造L-古洛糖酸内酯氧化酶的哺乳动物，它肯定不是一种“维生素”。这些哺乳动物，从不患坏血病，即使饮食一种完全不含维生素C的饮食。
当这种指出的每日许多克的肝脏代谢物—抗坏血酸的合成，和推荐作为人类营养性足够的每日60毫克的量相比较，（Food and Nutrition Board24），有里有一个33~250倍的差异。自从维生素C膳食失调假说在1912年问世，重点一直在预防或治疗显性坏血病的症状，而忽视抗坏血酸在生命过程的许多其他基本的功能。一个平民每天给予几毫克的维生素C将不会有典型的坏血病症状，但，仍然会患严重的亚临床生化坏血病。
自1912年，从未受过挑战，被广泛接受的维生素C假说，诞生于这样的时期，现在广泛接受的生物化学和遗传概念未知道或未被认可。Archibald Garrod 关于“先天性代谢错误”的著名演说，只在早前四年的1908年发表，在这里，他指出酶的失落会引起疾病。这个革命性的医学概念，被忽视和轻视了几十年。抗坏血酸的发现、分离和合成仍是20年之后的事情。现代遗传信息转移的观点尚未问世。非常清楚，60年长的维生素假说，因为其固有的，趋向微量和缓解急性临床坏血病的倾向，是一种对我们当代知识的完全的过度简单化，以及轻视了慢性抗坏血酸摄入不足对人体内抗坏血酸的多项生理功能的长期影响。
生物 出现的时间（106年） 抗坏血酸合成的位置
鱼 425 肾
两栖动物 325 肾
爬行动物 205 肾
哺乳动物 165 肝
Irwin Stone is a chemical engineer by training, a biochemist by vocation and a paleopathologist by avocation. He started working on ascorbic acid in 1934 and received the first U.S. Patents for its use as a food antioxidant. Worldwide use of this process has been a factor in the virtual elimination of frank clinical scurvy in the developed countries. In 1965-67 he published a series of papers describing the genetic, liver-enzyme disease, Hypoascorbemia and its significance in Medicine. This new genetic approach supplies the rationale for the use of massive doses of ascorbic acid in Orthomolecular Therapy. He is now Research Director of Megascorbic Research, Inc.
Ascorbic acid is a vital, ubiquitous substance, in the life process. All living organisms either make it, get it in their foodstuffs or they perish. The enzyme systems for the production of ascorbic acid are of ancient origin and were formed very early in the development of the life process on this planet, probably while the most highly developed forms were still primitive unicellular forms.
The evidence of both plant and animal embryology corroborates this viewpoint as the dormant plant seed and animal egg are devoid of ascorbic acid. There is an immediate production of ascorbic acid in the germinating seed or developing egg, even when the embryo is nothing more than a cluster of a few cells.
Its widespread occurrence in all present day multicellular organisms, both plant and animal, also testify to this. We can also infer that ascorbic acid production was well developed before the living organisms diverged into the plant and animal forms, Stone.1
Chemically, ascorbic acid is a simple carbohydrate material, related to glucose, of rather unique properties. The presence of the ene-diol group in the molecule confers electron lability, which makes it a member of an oxidation-reduction system having electron donating and electron accepting properties, see Fig. 1. At a submolecular level, the living process is nothing more than a stepwise orderly, transfer of electrons, so that the presence of an electron-labile system such as ascorbic acid in a living organism acting in concert with other ancient oxidative-reductive systems, aids in maintaining electron-transfer efficiency in the living process.
Figure 1. The Reversal Oxidation-Reduction
If we rely on the examination of present day living animals for their ascorbic acid production to estimate its occurrence in the fossil record, we accumulate much interesting and enlightening data on the evolution of the enzyme systems involved. Based on the known accuracy of the genetic transfer of information, we can assume that the enzyme systems and their bodily location in present living animals have changed little from their ancient representatives.
Every one of the primitive invertebrates and lower organisms so far examined showed the presence of ascorbic acid, Bourne and Allen;2 Bourne.3 In nearly all the vertebrates examined, ascorbic acid production is the normal state. Those few species that cannot make their own ascorbic acid are suffering from a genetic defect in their enzyme-production systems and must receive a supply of ascorbic acid from their foodstuffs or die of scurvy.
Table 1 shows the locus of the ascorbic and enzyme system during the course of evolution of the vertebrates from the fishes to the primates, based on data obtained by the examination of present day animal forms, Chatterjee et al.1 Roy and Guha5; Chaudhuri and Chatterjee.6
The locus of the enzymes for ascorbic acid production in the cold-blooded vertebrates, the fishes, the amphibians and the reptiles, are in the kidneys. The more highly active warm-blooded mammals all synthesize their ascorbic acid in their liver. One of the main functions of ascorbic acid in animal physiology is the maintenance of biochemical homeostasis under stress. The greater the stress an animal undergoes, the more ascorbic acid it produces.
About 165 million years ago, when Nature had the evolution of the more active and stressful mammals in view, an important morphological and physiological decision had to be made. The kidneys, while adequate as the site of ascorbic acid synthesis for the rather sluggish cold-blooded vertebrates, were inadequate for the increased ascorbic acid needs of the more highly stressed mammals. The successful solution of this problem was the transfer of the enzymes for the production of ascorbic acid from the relatively small biochemically-crowded kidney to the more spacious liver, which is the largest organ of the body. All present day mammals capable of synthesizing ascorbic acid are liver producers because any ancient form which did not make this transfer was so biochemically handicapped that they were eliminated by the forces of Evolution.
The present day birds, whose ancestors appeared about the same time as the mammals, still show this kidney-liver transition, Chaudhuri and Chatterjee.6 The older order of present day birds, such as the ducks, pigeons and hawks, synthesize their ascorbic acid in their kidneys, while in the more recent order of the perching and song birds, the Passeriformes, some produce ascorbic acid both in their kidneys and livers, others only in their liver. Some, like man, are incapable of synthesizing ascorbic acid at all.
As Evolution proceeded, the primates appeared about 65 million years ago and like other mammals should be capable of synthesizing ascorbic acid in their livers. However, something happened during the evolution of the primates because it has been known for thousands of years that Man, unlike other mammals, was susceptible to scurvy.
Up until 1907 scurvy was considered a completely human disease as no other animal was known to be susceptible to it. In 1907, Holst and Frohlich7, working on ship beri-beri contracted aboard ship for the Norwegian Fishing Fleet, wanted a small mammal to substitute as a test animal for the pigeons then used. They fed guinea pigs the test diet, which produced beriberi in their pigeons, and much to their surprise, scurvy resulted instead. Later it was shown that laboratory monkeys were also susceptible to scurvy. Man, guinea pigs and certain monkeys, unlike other mammals, cannot make their own ascorbic acid.
In 1912 the vitamin hypothesis was postulated (Funk8), part of which stated that scurvy was a deficiency disease caused by a lack of an unknown water-soluble substance, called Vitamin C, in the diet. Twenty ears later in 1932 (Svirbely and Szent-Györgyi ), it was demonstrated that ascorbic acid was identical with Vitamin C. Burns10 in 1959 Showed that the basic biochemical lesion in the few mammals susceptible to scurvy was due to their inability to produce the active enzyme, L-gulonolactone oxidase, involved in the in the mammalian conversion of blood glucose to ascorbic acid, in their livers. This synthesis, involving four enzymes, is illustrated in Fig 2. Man has the first three enzymes in his liver but it is the missing fourth enzyme, which completely blocks the liver production of ascorbic acid.
Figure 2. Man has the first three enzymes in his liver but it is the
Up until 1965 it was assumed that all primates were unable to produce their own ascorbic acid and were thus susceptible to the disease, scurvy. It was pointed out (Stone1) that this was merely an assumption and one which had never been tested. It was suggested that the whole order of the primates should be examined for the presence of L-gulonolactone oxidase in their livers. If this was done, then the data obtained might be useful in pinpointing, in time, when the mutation occurred. Thus it might be possible to determine in which primate ancestor of man this important enzyme system was lost.
This suggestion was picked up and tests were reported from Harvard (Elliott et al.11) in 1966 and Yerkes Primate Research Center in 1969 (Nakajima et al.12) wherein it was indicated that all of the monkeys examined, which were members of the suborder, Prosimii, showed active enzyme, L-gulonolactone oxidase, in their livers while the livers of those members of the suborder Anthropoidea are inactive. While the data is not fully complete for all members of the primate order, the present sampling indicates that the dividing line between those primates which are susceptible to scurvy and those that arc not, is likely to be between the two main suborders, the Prosimii and the Anthropoidea.
This is illustrated in Fig. 3 showing a chart of the fossil record of the primates as devised by Simons.13 The second column from the right is a listing of the families of the present day primates. The column on the far right, marked “Liver GLO” contains the results of the recent examination of the primate livers for the presence of the active enzyme, L-gulonolactone oxidase. In all the primates thus far examined, those in the six genera of the suborder, Anthropoidea, lack this enzyme in their liver while those of the four genera Prosimii have the active enzyme and can synthesize their own ascorbic acid. While more members of other Prosimii families should be examined such as Lemuridae, Tarsiidae and Daubentoniidae, the present indications are that the division between the Prosimii and the Anthropoidea is not only morphological but also in this important physiological parameter.
Figure 3. Chart of the Fossil Record of the Primates with the
Occurrence of Active L-Gulonolactone Oxidase
If we follow the arrow and extrapolate this dividing line back into time on this chart, then we arrive at a point between the late Cretaceous and late Paleocene where this mutation which destroyed the gene for the synthesis of the enzyme protein, L-gulonolactone oxidase, appears to have occurred. This happened not long after the primates appeared on the scene, about 58 to 63 million years ago in the vicinity of the spurred circle, in the primate ancestor whose progeny evolved into the suborder Anthropoidea.
It is probably more than coincidental, that in the neighborhood of the late Cretaceous period, when this primate genetic accident occurred, there was a brief interval when many other organisms underwent a severe attenuation in diversity or became extinct. This included many invertebrate forms and notably the vertebrate dinosaurs which suddenly disappeared from the fossil record. Russell and Tucker14 in 1971 suggested that a nearby supernovae explosion, with its liberation and absorption by the earth’s atmosphere of large fluxes of cosmic rays gamma rays and x-rays, might have produced climatic effects so drastic as to have caused the extinction of many animals including the cold-blooded dinosaurs. If such an astronomical event occurred, then the random absorption of some of this high energy radiation may have been instrumental in mutating the primate gene for the synthesis of the enzyme protein, L-gulonolactone oxidase, resulting in an inactive enzyme.
Thus a conditional lethal mutation (Gluecksohn-Waelsch15) happened to this primitive primate. The destruction of so vital a biochemical process would have had lethal consequences were it not for the fact that it occurred to an arboreal animal living in a tropical or semi-tropical environment where plenty of foodstuffs containing ascorbic acid were available throughout the entire year. The diet of the mutated primate may not have supplied as much ascorbic acid as its previous liver synthesis, but it was sufficient for survival. Bourne16 in 1944 showed that a modern gorilla, living in its natural habitat, would obtain 4.5 grams of ascorbic acid per day from its foodstuffs.
Pauling17 in 1970, basing his calculations on the caloric content and ascorbic acid levels in raw plant foods, concluded that the range of the optimum intake is about 2.3 to 9.5 grams per day. He also pointed out, while the range of the B vitamins in 110 raw plant foods supplying 2,500 calories was only two to four times the recommended dietary allowances, the corresponding ratio for ascorbic acid was 35 times that recommended, 2,300 milligrams versus 60 milligrams a day.
Pauling indicated in 1968 that this mutation may have had survival value at the time because it freed the biochemical machinery for other purposes and conserved energy. This survival value was lost as soon as the progeny of this mutated animal, evolving into the future genus, Homo, left the trees, moved into temperate climes and changed its diet to one where high levels of ascorbic acid were not dominate the year round.
Man still carries this defective gene and it has no survival value for modern Man. In fact, in the course of prehistory and during historical times, it has been a severe handicap and the side effects of this defective gene have resulted in the deaths of more individuals, caused more sickness and suffering and have changed the course of history more than any other single factor.
As a result of these evolutionary studies, it was indicated by Stone19 in 1966 that due to this defective gene, which produced an inactive enzyme, present day humans are suffering from a mammalian inborn error of carbohydrate metabolism which was named, Hypoascorbemia Scurvy is actually the sequelae of this genetic liver-enzyme disease which makes it necessary for man to obtain ascorbic acid from exogenous sources, Stone.20 For the past 60 years, ascorbic acid has been regarded as “vitamin C” when actually it is a liver metabolite and certainly not a “vitamin” for the myriad of mammals having the intact gene for L-gulonolactone oxidase. These mammals never contract scurvy, even on a diet completely free of vitamin C.
If correction of this inborn error of carbohydrate metabolism is defined as a need to supply, to the individual, the daily amount of ascorbic acid the human liver would be producing, if the intact gene were present, then the daily production of this liver metabolite would be about two to four grams, based on data for the unstressed rat (Burns et al.21 Saloman and Stubbs22) and at least 15 grams per day under stress, Conney et al.23
When this indicated daily multigram synthesis of the “liver metabolite,” ascorbic acid, is compared with the daily amount of “vitamin C,” 60 milligrams (Food and Nutrition Board24), recommended as nutritionally adequate, for humans, there is a 33 to 250 fold disparity. Ever since the vitamin C-dietary disorder hypothesis was postulated in 1912, the emphasis has been on the prevention or cure of the symptoms of frank clinical scurvy to the neglect of the many other basic functions of ascorbic acid in the living process. A subject given the daily few milligrams of vitamin C will not show the classic symptoms of frank clinical scurvy but may still be suffering from severe subclinical biochemical scurvy.
The vitamin C hypothesis which has had unchallenged acceptance since 1912 originated at a time when modern, widely accepted biochemical and genetic concepts were either unknown or unrecognized. The classic lectures of Sir Archibald Garrod25 on the “Inborn Errors of Metabolism,” in which he showed that missing enzymes could cause diseases, were delivered only four years earlier in 1908. This revolutionary medical concept was ignored and neglected for decades. The discovery, isolation and synthesis of ascorbic acid were still twenty years in the future. The modern views on genetic information transfer were unknown. Clearly the 60-year old vitamin C hypothesis with its built-in orientation toward minute doses and the alleviation of acute clinical scurvy is a gross oversimplification of our present knowledge and subordinates the long term effects of chronic inadequate ascorbic acid intakes on the multitude of physiological functions of ascorbic acid in the human body.
In the clinical research of the past 40 years there have been hundreds of papers written to find the daily minimum level of ascorbic acid needed to prevent or eliminate the classic symptoms of frank clinical scurvy. However, you will not find a single paper reporting on the long-term effects of continued administration of ascorbic acid based on time levels produced endogenously in the mammalian liver. These high levels of ascorbic acid production have served so well in maintaining biochemical homeostasis under stress for the past 165 million years during the evolution and world dominance of the mammals. After nearly 60 million years since this primate mutation occurred, it is only in the last 40 years, since the synthetic production of unlimited quantities of ascorbic acid, that it has become possible to fully correct this genetic liver-enzyme disease.
These genetic concepts provide the rationale for the use of large doses (megascorbic levels) of ascorbic acid and open up wide vistas of research in preventive medicine and therapy, Stone,26 In the few areas where megascorbic therapy has been tried, it has been eminently successful; in the treatment of the viral diseases, in glaucoma, in schizophrenia and as a detoxicant. Research on other applications of these genetic principles will lead to the megascorbic prophylaxis and megascorbic therapy of many other disease states, Stone.2
Evidence is presented that time enzyme systems for the important synthesis of ascorbic acid are of very ancient origin, beginning long before time plant and animal lines diverged. The progressive vertebrate evolution of these enzymes are traced through the fishes, amphibians, reptiles, birds and mammals. Shortly after the appearance of the primates, a genetic mutation occurred on the gene for the liver enzyme L-gulonolactone oxidase, which destroyed this animal’s ability to produce ascorbic acid from blood glucose. The progeny of this mutated animal developed in to time present day members of the primate suborder, Anthropoidea. The non-mutated primates are the ancestors of the present suborder, Prosimii.
Extrapolation of this data into the primate fossil record indicates the mutation to have occurred in the period the same nearby supernovae explosion which was possibly responsible for the extinction of the dinosaurs and the disappearance of many invertebrates in the late Cretaceous.
Members of the genus Homo, present day Man, still carry this defective gene and during prehistoric and historical times it has been responsible for more deaths, more sickness and human misery and more changes in history, than any other single factor.
The vital importance of ascorbic acid in many phases of human physiology has been underrated for the past 60 years because in 1912, 20 years before its discovery and synthesis, it was designated a “vitamin” for the treatment of frank clinical scurvy which was considered a simple dietary disturbance.
Actually, ascorbic acid is a liver metabolite produced in nearly all mammals in large daily amounts. Because of this defective gene Man is suffering from a mammalian genetic liver-enzyme disease, a true “inborn error of carbohydrate metabolism,” named Hypoascorbemia. Scurvy is not a distinct disease entity but merely the final fatal sequelae of uncorrected Hypoascorbemia.
This genetic approach provides the rationale for the use of large daily doses of ascorbic acid and opens wide vistas of research for its application to preventive medicine and therapy.
LOCUS OF ASCORBIC ACID ENZYMES
Time of Appearance
Site of Ascorbic
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From Orthomolecular Psychiatry, 1972, Volume 1, Numbers 2 & 3, pp. 82-89.