W R U A R Y , 1949
BRITISH ANTI-LEWISITE R. A. PETERS University of Oxford, Oxford, England
S c I m m sometimes counteracts its owi potentially dangerous discoveries; the fact that we now have an antidote to the arsenical war gas, lewisite, called British anti-lewisite (BAL) means that it is no longer ~rofitahleto use arsenical vesicants of this type in warfare. The work which led to the discovery of BAL had its origins firmly rooted in purely academic research. In fact, so unlikely did any connection between the hiochemists' work and therapy of a lewisite burn appear to be that, at an essential stage in the war research, an influential body decided officially to discontinue the investigation. Again, no one would have predicted that the financial support of war researches would result in a drug of value in medical practice. To understand the way in which this antidote acts requires some preliminary knowledge of modern biochemistry. The transformation of chemical substances, such as foodstuffs, in the course of their utilization in life, is brought about by special biochemical tools. These belong to the class of enzymes. Modern research has discovered many enzymes in the timues of the body, most of them with very specialized chemical
functions. The power of movement is made possible by the transformation of the foodstuff, sugar, to the ultimate stages of the gas, carbon dioxide, and water; this liberation of energy takes place through a series of highly specialized and exact biochemical stages. Since this process is essential to l i e it follows that, if one of these stages fails through interference with its special enzyme, the course of sugar degradation is arrested; hence, there must also follow the arrest of the living process in the tissue with the gradual development of abnormal biochemical changes, known better as pathological processes. An example of this may be considered. It is known that convulsions occur in animals when they are fed upon diets deficient in the anti-beriberi vitamin, vitamin B1 or aneurin. Biochemical research; much of it in Oxford, has shown that these convulsions are due to actual lack of vitamin B, in the brain tissue itself. This is because this vitamin is an essential component of the "pyruvate" enzyme; in its absence the enzyme does not function and consequently the degradation of sugar is stopped a t the pyruvic acid stage. This arrest is fatal to the normal functioning of the brain tissue.
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JOURNAL OF CHEMICAL EDUCATION
Proof of the arrest a t this stage is readily found, because the unchanged pyruvic acid even accumulates in the blood s t r e a k It is this same important enzyme which is a.t,t,acked ... . ..-. -- - bv lewisite. and it was used as a test enzvme. WARTIME RESEARCH
that in the tissue, the poisoning arsenic could be removed. REVERSALsOF SYMPTOMS
This led to a synthesis of the new compound BAL, whose chemical name is 2,3-dimercaptopropanol. I t is a mobile oil, passing readily through skin, and it is simpler chemically than its name suggests, being just glycerol with two OH groupings replaced by SH. I t forms an extremely firm compound vith lewisite and mas proved in the test tube t o remove arsenic combined with the pyruvate enzyme, thus setting this free to resume its normal activities. I n man, BAL mill not only prevent vesication when applied before the lewisite, but in agr'eement with theory, even vhen applied two hours after contamination of the skin with lemisite, it will reverse the commencing reddening and swelling. The BAL-arsenic compound is removed from the skin and excreted in the urine. I t will also save animals from the toxic effectsof lewisite, even when given after the onset of severe signs of diarrhea. This discovery has great possibilities in medicine which are being pursued by the British Medical Research Council. Occasionally as the result of treatment by arsenical drugs, sensitive patients get a horrible skin condition, called exfoliative arsenical dermatitis; such patients with the whole skin in eruption are very difficult to cure owing to the avidity 116th which the arsenic clings to the skin. By the use of BAL, in the form of an oily injection designed in the United States, these patients can he restored to health in three weeks to a month.
Very early, indeed, in World War 11, research m s initiated by the Oxford University Biochemistry Department, supported by Britain's Ministry of Supply. Its object was to find antidotes to the skin-blistering agents mustard gas and lewisite. The team which worked at this included mainly members of the staff of the department. The two guiding ideas were that these chemical warfare substances attacked the pyfivate enzyme and that the site of attack in the enzymes mas a specialized sulfur grouping, known as the sulfydril group, SIX. Both of these ideas had their origin in previous work in this laboratory. The idea that the attack was upon a sulfur grouping dated back to about 1923, to work carried out independently in Oxford and in the United States on different kinds of arsenical substances. It received support from much evidence in the intervening years; that the pyruvate enzyme such as is found in brain might be susceptible and that this might he connected with vesication mas suggested in 1936. In World War I1 it was soon confirmed that the pyruvate enzyme mas extremely sensitive to attack by lewisite, and it was found to possess a sulfur grouping essential to its activity. It was further found that arsenical poisoning caused a rise in the pyruvic acid content in blood, such as takes place in anenrin deficiency. From this it might he thought that some compound containing the SH group should act a.s an antidote by attracting away the arsenic from the tissue enzyme. ACTION OF BAL Nevertheless, substances containing one SH group First Step would not act as antidotes to lewisite. The arsenic was too tightly bound by the enzyme. Some ten months after the start of xvar, two of our T i w e ensyme ~ ~ ~+: 2HCI ~ ~ ~ l for skin). ,, known as keratin. Briefly they found that the arsenical compound did combine withthe sulfydril Step groups in the hair keratin; further (and this was the crucial point), one arsenic atom combined with two C&.SH sulfur groupings a t once. This could only mean that I As.CH:CHCl + CH.SH = it was formine a chemical ring. At once it could be 1 CH~OH seen why thearsenic was too tightly bound with the 2,3-dimeroapto ropanol enzyme to be attracted away by the addition of other sulfydril compounds, because ring formation in chemiSH ' ? H ' . 3 ~ s ~ ~ : ~ ~ ~ cal compounds is known to lead to greater stability. Tissue enzyme + CH.8 The idea arose that if a compound containing two SH (free enzyme) ~ F I&LOq groups could be made capable of forming a more tightly BAL-lewislte fixed compound with the arsenic in the lewisite than . A ,
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