Binding of dimethylarsinous acid to cys-13alpha of rat hemoglobin is responsible for the retention of arsenic in rat blood.
The metabolism, disposition, and carcinogenicity of arsenic differ dramatically between humans and rats. To understand the molecular basis of these differences, we have characterized arsenic species in rats that were treated with inorganic arsenate (iAsV), monomethylarsonic acid (MMAV), or dimethylarsinic acid (DMAV) for up to 15 weeks. Arsenic significantly accumulated in the red blood cells (RBCs) of rats in the form of hemoglobin (Hb) complexed with dimethylarsinous acid (DMAIII), regardless of whether the rats were treated with iAsV, MMAV, or DMAV, suggesting rapid methylation of arsenic species followed by strong binding of DMAIII to rat Hb. The binding site for DMAIII was identified to be cysteine 13 in the alpha-chain of rat Hb with a stoichiometry of 1:1. Over 99% of the total arsenic (maximum 2.5-3.5 mM) in rat RBCs was bound to Hb for all rats examined (n = 138). In contrast, only 40-49% of the total arsenic (maximum approximately 10 muM) in rat plasma was bound to proteins. The ratios of the total arsenic in RBCs to that in plasma ranged from 88-423 for rats that were fed iAsV, 100-680 for rats that were fed MMAV, and 185-1393 for rats that were fed DMAV, when samples were obtained over the 15-week exposure duration. Previous studies have shown an increase in urothelial hyperplasia in rats fed DMAV. This is the first article reporting that treatment with iAsV in the drinking water also produces urothelial hyperplasia and at an even earlier time point than dietary DMAV. Dietary MMAV produced only a slight urothelial response. A correlation between the Hb-DMAIII complex and urothelial lesion severity in rats was observed. The lack of cysteine 13alpha in human Hb may be responsible for the shorter retention of arsenic in human blood. These differences in the disposition of arsenicals may contribute to the observed differences between humans and rats in susceptibility to arsenic carcinogenicity.
Lu
Meiling
M
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G3 Canada.
Wang
Hailin
H
Li
Xing-Fang
XF
Arnold
Lora L
LL
Cohen
Samuel M
SM
Le
X Chris
XC
D000595:Amino Acid Sequence; D000818:Animals; D001151:Arsenic / Q000097:blood*; D001665:Binding Sites; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000378:metabolism*; D005260:Female; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D021241:Spectrometry, Mass, Electrospray Ionization
D006454:Hemoglobins; C472511:dimethylarsinous acid; D002101:Cacodylic Acid; D003545:Cysteine; D001151:Arsenic