Inorganic arsenic that is ingested through drinking water or inhalation is metabolized by biological methylation pathways into organoarsenical metabolites. It is now becoming understood that this metabolism that was formerly considered to be detoxification may contribute as much or more to increasing the toxicity of arsenic. One proposed mode of the toxic action of arsenic and its organoarsenic metabolites is through its binding to proteins and inactivating their enzymatic activity. The classic case has been considered the affinity of the proximal 1,3 sulfhydryl groups of the lipoic acid cofactor of the pyruvate dehydrogenase complex for arsenic. A 2:1 stoichiometry of sulfhydryl to arsenic groups has been measured in proteins and arsenical complexes can be synthesized using free D,L-lipoic acid. The relative importance of this site for arsenic binding has come in to question through the use of methylating bifunctional arsenic complexes that suggested the methylation of an active site histidine may also be important, and the suggestion that arsenic inhibits the pyruvate dehydrogenase complex indirectly by elevating mitochondrial hydrogen peroxide generation. In order to separate the effects of direct trivalent arsenite toxicity from that of hydrogen peroxide and activated oxygen, we studied the inhibition of the PDH complex under conditions that did not generate hydrogen peroxide but did expose the lipoic acid group in its reduced state to arsenicals. We also studied the effects of arsenicals in the inhibition of the α-ketoglutarate dehydrogenase complex. We found that only trivalent arsenical compounds inhibited the activity of both dehydrogenase complexes and only when the lipoic acid was in its reduced form. Arsenite inhibited both enzyme complexes approximately equivalently while monomethylarsenite inhibited the PDH complex to a greater extent than the KGDH complex -although both complexes were very sensitive to inhibition by this complex. Dimethylarsenite inhibition of both complexes was only observed with longer pre-incubation periods. Cumulative inhibition by the reduced arsenical was observed for all complexes indicating a binding mode of inhibition that is dependent upon lipoic acid being in its reduced state. KeywordsArsenic; pyruvate dehydrogenase; alpha ketoglutarate dehydrogenase; lipoic acid; methyl arsenic Fax. (406) 243-4227, E-mail address: brooke.d.martin@umontana.edu. Only reduced arsenic species were able to inhibit the enzymatic action of the pyruvate and α-ketoglutarate dehydrogenase complexes and only under condition that poised the enzyme complex in a catalytic state that contained reduced lipoic acid groups. Monomethylarsenite was by far the most potent compound toward enzyme inhibition.
A 23-year-old man referred by his primary care physician presented with a 1.5-year history of progressive left ankle pain and swelling. He recalled no history of trauma other than stepping on a horseshoe crab when he was 8 years old and having the tail removed in a local emergency department. He denied recent fevers, chills, night sweats, weight loss, or weight gain. Physical examination revealed substantial nonpitting edema around the hindfoot region extending up the distal 1 .3 of his leg. There was no skin discoloration. He had mild tenderness to palpation along the peroneal and posterior tibial tendons. There was normal strength and sensation in the foot and leg. No lymphadenopathy was noted. His laboratory values, including complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), uric acid, rheumatoid factor, and Lyme titer were all within normal limits. Imaging studies, including MRI (Fig. 1), CT scan (Fig. 2), and bone scan (Fig. 3), were performed. Based on the history, physical examination, laboratory tests, and imaging studies, what is the differential diagnosis? Imaging InterpretationSagittal T1-weighted (Fig. 1A), sagittal T2-weighted fat-suppressed (Fig. 1B), and axial T1-weighted fatsuppressed contrast enhanced (Fig. 1C) MR images of the ankle showed a T1 hypointense and T2 hyperintense soft tissue mass remodeling the undersurface of the sustentaculum tali. There was a small irregular central area of low signal consistent with calcification.Coronal ( Fig. 2A) and sagittal (Fig. 2B) reformatted CT images of the ankle showed an area of smooth osseous remodeling at the inferior aspect of the sustentaculum tali. There was a 7-9 4-mm triangular calcification adjacent to the area of remodeling.Radionuclide bone scan (Fig. 3) of the bilateral feet and ankles showed radiotracer uptake in the left posterior calcaneus.Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.
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