title: Generation of thioarsenicals is dependent on the enterohepatic circulation in rats.
abstract: Three minor sulfur-containing arsenic metabolites: monomethylmonothioarsonic acid (MMMTA(V)), dimethylmonothioarsinic acid (DMMTA(V)), and dimethyldithioarsinic acid (DMDTA(V)) were recently found in human and animal urine after exposure to inorganic arsenic. However, it remains unclear how the thioarsenicals are formed in the body and then excreted into the urine. It is hypothesized that the generation of thioarsenicals occurs during enterohepatic circulation. To address this hypothesis, male Sprague Dawley (SD) rats and Eisai hyperbilirubinuric (EHB) rats (with deficiency of multidrug resistance-associated protein 2) were orally administered a single dose of inorganic arsenite (iAs(III)) at 3.0 mg kg(-1) of body weight. Five hours after dosing, less than 1.0% of the dose was recovered in the bile of EHB rats, while more than 27% of the dose was recovered in the bile of SD rats, with the majority being monomethylarsinodiglutathione [MMA(SG)(2)] with a small amount of arsenic triglutathione [iAs(SG)(3)]. During the early time periods (3 h and 6 h) the arsenic levels in the liver, red blood cells (RBCs) and plasma of EHB rats were higher than those of SD rats, and approximately 76% and 87% of the dose was recovered in the RBCs of SD and EHB rats, respectively, at day 5 after dosing. However, there were no significant differences in arsenic concentration in urine between the two types of animal. Regarding the arsenic species in the urine of both types of rat, significant levels of thiolated arsenicals MMMTA(V) and DMMTA(V) were detected in SD rat urine, however in EHB rat urine only low levels of DMMTA(V) were detected. The present result of the metabolic balance and speciation study suggests that the formation of MMMTA(V) and DMMTA(V) in rats is dependent on enterohepatic circulation. In addition, in vitro experiments indicated that arsenicals excreted from bile may be transformed by gastrointestinal microbiota into MMMTA(V) and DMMTA(V), which are then absorbed into the bloodstream and finally excreted into the urine.
authors.affiliation: Department of Pharmacology, Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Na
authors.initials: N
authors.lastname: Bu
authors.forename: Hong Yun
authors.initials: HY
authors.lastname: Wang
authors.forename: Wen Hui
authors.initials: WH
authors.lastname: Hao
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Shi
authors.initials: S
authors.lastname: Xu
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.forename: Yasumi
authors.initials: Y
authors.lastname: Anan
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Ogra
authors.forename: Yi Jia
authors.initials: YJ
authors.lastname: Lou
authors.forename: Hua
authors.initials: H
authors.lastname: Naranmandura
mesh_terms: D000818:Animals; D001152:Arsenicals / Q000008:administration & dosage / Q000378:metabolism*; D018053:Arsenites / Q000008:administration & dosage / Q000378:metabolism; D001646:Bile / Q000378:metabolism; D002101:Cacodylic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D004764:Enterohepatic Circulation; D017353:Gene Deletion; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D001149:Arsenates
chemical_list: D001152:Arsenicals; D018053:Arsenites; D002101:Cacodylic Acid; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013438:Sulfhydryl Compounds; C518668:dimethyldithioarsinic acid; C518667:dimethylmonothioarsinic acid; D001149:Arsenates; C552934:monomethylmonothioarsonic acid; C015001:arsenite