title: Proposal for novel metabolic pathway of highly toxic dimethylated arsenics accompanied by enzymatic sulfuration, desulfuration and oxidation.
abstract: The International Agency for Research on Cancer (IARC) has concluded that dimethylarsinic acid [(CH3)2AsO(OH), DMA(V)], a main metabolite of inorganic arsenic, is responsible for carcinogenesis in urinary bladder and lung in rodents, and various modes of carcinogenic action have been proposed. One theory concerning the mode of action is that the biotransformation of dimethylarsinous acid [(CH3)2AsOH, DMA(III)] from DMA(V) plays an important role in the carcinogenesis by way of reactive oxygen species (ROS) production. Furthermore, dimethylmonothioarsinic acid [(CH3)2AsS(OH), DMMTA(V)], a metabolite of DMA(V), has also been noted because of its higher toxicity. However, the metabolic mechanisms of formation and disappearance of DMA(III) and DMMTA(V), and their toxicity are not fully understood. Thus, the purpose of the present study was to clarify the mechanism of metabolic formation of DMMTA(V) and DMA(V) from DMA(III). The in vitro transformation of arsenicals by treatment with liver homogenate from rodents and sulfur transferase was detected by HPLC-ICP-MS and HPLC-tandem MS. DMMTA(V) is produced from DMA(III) but not DMA(V) by cellular fractions from mouse liver homogenates and by rhodanese from bovine liver in the presence of thiosulfate, a sulfur donor. Not only DMMTA(V) thus produced but also DMA(III) are re-converted into DMA(V) by an in vitro addition of S9 mix. These findings indicate that the metabolic process not only of DMA(III) to DMA(V) or DMMTA(V) but also of DMMTA(V) to DMA(V) consists of a complicated mode of interaction between monooxygenase including cytochrome P450 (CYP) and/or sulfur transferase.
authors.affiliation: Laboratory of Environmental Toxicology and Carcinogenesis, Nihon University School of Pharmacy, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Shimoda
authors.affiliation: Laboratory of Environmental Toxicology and Carcinogenesis, Nihon University School of Pharmacy, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kurosawa
authors.affiliation: Laboratory of Environmental Toxicology and Carcinogenesis, Nihon University School of Pharmacy, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kato
authors.affiliation: Research Center for Occupational Poisoning, Kansai Rosai Hospital, Hyogo 660-8511, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Endo
authors.affiliation: Laboratory of Environmental Toxicology and Carcinogenesis, Nihon University School of Pharmacy, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan. Electronic address: yamanaka.kenzo@nihon-u.ac.jp.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Yamanaka
authors.affiliation: Department of Preventive Medicine and Environmental Health, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
authors.forename: Ginji
authors.initials: G
authors.lastname: Endo
mesh_terms: D065767:Activation, Metabolic / Q000187:drug effects; D000818:Animals; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000633:toxicity; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008813:Mice, Inbred ICR; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D013455:Sulfur / Q000378:metabolism*; D013884:Thiosulfate Sulfurtransferase / Q000378:metabolism*; D001149:Arsenates
chemical_list: D002101:Cacodylic Acid; D013455:Sulfur; D013884:Thiosulfate Sulfurtransferase; C472511:dimethylarsinous acid; C518667:dimethylmonothioarsinic acid; D001149:Arsenates
keywords: CYP; Dimethylarsinic acid; Dimethylarsinous acid; Dimethylmonothioarsinic acid; Rhodanese