British anti-Lewisite
By Domingo Tabangcura, Jr. and G. Patrick Daubert, MD


Biochemistry

BAL has a 3-carbon backbone with two sulfhydryl (-SH) groups and a hydroxyl group (figure 3). Early research into the mechanism of effectiveness of BAL came from work with arsenic and sulfur groups in hair protein.[2] It was surmised at the time that metals bind to the sulfhydryl groups of various enzymes as a mechanism for their significant toxicity. The Oxford Group had been testing glutathione (C10H17N3O6S a polypeptide of glycine, cystine, and glutamic acid) with one sulfhydryl group in the treatment of arsenic poisoning without much success.[3] Using the human hair with abundant thiol groups they were able to elucidate the mechanism for BAL. As time progressed it was found that the sulfhydryl groups of lipoic acidwas the target for arsenic poisoning.[8] Lipoic acid is a key component of two important enzymes: pyruvate dehydrogenase (PDH) and alpha-ketogluterate dehydrogenase (KDH). PDH converts the end product of glycolysis to acetyl coenzyme A, which can then enter the tricarboxylic acid (TCA) cycle. KDH is an enzyme with the TCA cycle. Lipoic acid is an 8-carbon dithiol that is covalently linked to one subunit of the PDH and KDH complex (figure 4). In the presence of arsenic, the two sulfhydryl groups bind with arsenic to form a six-membered ring (figure 5). BAL presents two sulfhydryl groups to the bound arsenic-lipoic acid and forms a more stable five-membered ring[8] (figure 6) thereby freeing PDH and KDH from arsenic inhibition. As mentioned previously, other metals also form complexes with sulfhydryl groups. The most stable complexes between BAL and metal ions are formed with Class B metals (arsenic, mercury, and gold). Lead is a Class A metal and chelation is best accomplished by adding a second chelator such as meso-2,3-dimercaptosuccinic acid (DMSA) or ethylenediaminetetraacetic acid (EDTA).[9, 10]


Figure 3. BAL, British anti-Lewisite 		 
Figure 4. Lipoic acid attached to pyruvate dehydrogenase (PDH)



Figure 5. Six-membered ring formed by arsenic and lipoic acid 		 
Figure 6. Favored 5-membered ring of BAL and arsenic


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