Effects of trivalent antimony on human erythrocyte glutathione-S-transferases

✍ Scribed by Raymond Poon; Ih Chu

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: English
• Weight: 137 KB
• Volume: 14
• Category: Article
• ISSN: 1095-6670
• DOI: 10.1002/(sici)1099-0461(2000)14:3<169::aid-jbt7>3.0.co;2-l

✦ Synopsis

Trivalent antimony (SB ‫3‬ ) in the form of potassium antimony tartrate was found to be an inhibitor of glutathione-S-transferases (GST) from human erythrocytes with a 50% inhibition concentration (IC 50 ) of 0.05 mM. The inhibition was, however, incomplete with 15-20% of the GST activity remaining unaffected. In comparison, ethacrynic acid, a known inhibitor of GST, was tenfold more potent and affected close to 100% inhibition. Pentavalent antimony (SB ‫5‬ ) in the form of sodium stibogluconate had no effect on GST. Group V metalloids such as arsenite was slightly inhibitory, and arsenate was noninhibitory. When compared with five heavy metals, the inhibitory potency followed the order of SB ‫3‬ Ͼ Hg ‫2‬ , Cu ‫2‬ Ͼ Cd ‫2‬ Ͼ Cr ‫3‬ Ͼ Fe ‫2‬ . SB ‫3‬ inhibition of GST was competitive against the substrate 1-chloro-2,4-dinitrobenzene (CDNB) with an apparent K i of 0.018 mM. Increasing the glutathione (GSH) concentration, however, produced a biphasic response: at concentrations below 1 mM, GSH was noncompetitive against SB ‫3‬ , but at 1 mM and higher it was apparently competitive. A concurrent study of interactions between GSH, CDNB, and SB ‫3‬ showed that there was a significant nonenzymatic conjugation of CDNB at high GSH concentrations, which was suppressed by SB ‫3‬ . The presence of albumin (500 mg/dL), or up to 5 mM N-acetylcysteine, cysteine, or ethylenediamine tetraacetic acid (EDTA) did not protect GST from the inhibitory effect of SB ‫3‬ . The ability of erythrocyte GST to conjugate CDNB, which was measured directly by the formation of dinitrophenyl-glutathione (DNP-glutathione), was reduced by approximately 20 and 33%, respectively, in the presence of 2 and 10 mM SB ‫3‬ , and nearly abolished with the addition of 0.2 mM ethacrynic acid. Based on these inhibition characteristics and the preferential accumulation of SB ‫3‬ in mammalian erythrocytes, it may be deduced that in the case of high antimonial intake, for example, during therapeutic treatment of Leishmaniasis, SB ‫3‬ levels in erythrocytes may be high enough to depress GST activity, which might compromise the ability of erythrocytes to detox-