Reaction mechanism underlying the in vitro transformation of thioarsenicals.
Thioarsenicals have been paid much attention due to the toxicity of arsenic, since some of them are highly toxic and commonly found in the urine of mammals. We previously reported that thioarsenicals might be produced in red blood cells (RBCs). Here, we further characterized the mechanism underlying the production and metabolism of thioarsenicals in RBCs using 34S-labeled dimethylmonothioarsinic acid (34S-DMMTA(V)) and purified rat hemoglobin (Hb) or a rat RBC lysate. 34S-DMMTA(V) did not bind to Hb on incubation with purified rat Hb, remaining in its original form. However, when 34S-DMMTA(V) was incubated with a rat RBC lysate, only arsenic, i.e., not sulfur (34S), was detected in a form bound to Hb (As-Hb). In addition, another arsenic product containing sulfur (34S) in the molar ratio of 34S/As=2 was detected, which was assigned as dimethyldithioarsinic acid (DMDTA(V)), suggesting that arsenic does not bind to Hb in the form of 34S-DMMTA(V) but does so in the form of dimethylarsinous acid (DMA(III)). Namely, DMMTA(V) appeared to be hydrolyzed into dimethylarsinic acid (DMA(V)) and H34S-, and the released H34S- reacted with DMMTA(V) to produce DMDTA(V). Thus, DMMTA(V) was transformed into DMDTA(V) and DMA(V) (2DMMTA(V) ->DMDTA(V)+DMA(V)), the latter product being reduced to DMA(III) in the presence of GSH and bound to Hb. In a separate experiment, (H34S-DMMTA(V) was incubated with sulfide (Na2S) and GSH. Although DMMTA(V) was not transformed into DMDTA(V) in the presence of only Na2S or GSH, it was transformed into DMDTA(V) in the presence of both Na2S and GSH. Our results suggest that DMMTA(V) is hydrolyzed enzymatically into DMA(V) and sulfide, the former being reduced to DMA(III) and bound to Hb, and the latter reacting with DMMTA(V) to yield DMDTA(V). Thus, DMMTA(V) is transformed into DMDTA(V) and DMA(V) through a hydrolytic reaction in a manner similar to a disproportionation reaction, DMA(V) being reduced and bound to Hb (As-Hb), and DMDTA(V) being produced more in the presence of sulfides in the medium.
Graduate School of Pharmaceutical Sciences, Chiba University, Chuo, Chiba 260-8675, Japan.
Hua
H
Naranmandura
Noriyuki
N
Suzuki
Kazuo T
KT
Suzuki
D000818:Animals; D001152:Arsenicals / Q000097:blood* / Q000138:chemical synthesis; D001711:Biotransformation; D004912:Erythrocytes / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000097:blood* / Q000138:chemical synthesis
D001152:Arsenicals; D013438:Sulfhydryl Compounds