title: Bis-butanediol-mercapturic acid (bis-BDMA) as a urinary biomarker of metabolic activation of butadiene to its ultimate carcinogenic species.
abstract: Human carcinogen 1,3-butadiene (BD) undergoes metabolic activation to 3,4-epoxy-1-butene (EB), hydroxymethylvinyl ketone (HMVK), 3,4-epoxy-1,2-butanediol (EBD) and 1,2,3,4-diepoxybutane (DEB). Among these, DEB is by far the most genotoxic metabolite and is considered the ultimate carcinogenic species of BD. We have shown previously that BD-exposed laboratory mice form 8- to 10-fold more DEB-DNA adducts than rats exposed at the same conditions, which may be responsible for the enhanced sensitivity of mice to BD-mediated cancer. In the present study, we have identified 1,4-bis-(N-acetyl-L-cystein-S-yl)butane-2,3-diol (bis-BDMA) as a novel DEB-specific urinary biomarker. Isotope dilution high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry was employed to quantify bis-BDMA and three other BD-mercapturic acids, 2-(N-acetyl-L-cystein-S-yl)-1-hydroxybut-3-ene/1-(N-acetyl-L-cystein-S-yl)-2-hydroxy-but-3-ene (MHBMA, from EB), 4-(N-acetyl-L-cystein-S-yl)-1,2-dihydroxybutane (DHBMA, from HMVK) and 4-(N-acetyl-L-cystein-S-yl)-1,2,3-trihydroxybutane (THBMA, from EBD), in urine of confirmed smokers, occupationally exposed workers and BD-exposed laboratory rats. Bis-BDMA was formed in a dose-dependent manner in urine of rats exposed to 0-200 p.p.m. BD by inhalation, although it was a minor metabolite (1%) as compared with DHBMA (47%) and THBMA (37%). In humans, DHBMA was the most abundant BD-mercapturic acid excreted (93%), followed by THBMA (5%) and MHBMA (2%), whereas no bis-BDMA was detected. These results reveal significant differences in metabolism of BD between rats and humans.
authors: Department of Medicinal Chemistry and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, Sealy Center for Environmental Health and Medicine (SCEHM) and the Department of Preventive Medicine and Community Health, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA, Department of Pathology, University of Vermont, Burlington, VT 05405, USA and Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Srikanth
authors: S
authors: Kotapati
authors: Department of Medicinal Chemistry and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, Sealy Center for Environmental Health and Medicine (SCEHM) and the Department of Preventive Medicine and Community Health, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA, Department of Pathology, University of Vermont, Burlington, VT 05405, USA and Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Dewakar
authors: D
authors: Sangaraju
authors: Department of Medicinal Chemistry and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, Sealy Center for Environmental Health and Medicine (SCEHM) and the Department of Preventive Medicine and Community Health, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA, Department of Pathology, University of Vermont, Burlington, VT 05405, USA and Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Amanda
authors: A
authors: Esades
authors: Sealy Center for Environmental Health and Medicine (SCEHM) and the Department of Preventive Medicine and Community Health, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
authors: Lance
authors: L
authors: Hallberg
authors: Department of Pathology, University of Vermont, Burlington, VT 05405, USA and.
authors: Vernon E
authors: VE
authors: Walker
authors: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: James A
authors: JA
authors: Swenberg
authors: Department of Medicinal Chemistry and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, Sealy Center for Environmental Health and Medicine (SCEHM) and the Department of Preventive Medicine and Community Health, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA, Department of Pathology, University of Vermont, Burlington, VT 05405, USA and Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA trety001@umn.edu.
authors: Natalia Y
authors: NY
authors: Tretyakova
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism / Q000652:urine; D002070:Butadienes / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D002273:Carcinogens / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D001239:Inhalation; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D016273:Occupational Exposure; D051381:Rats; D012907:Smoking; D053719:Tandem Mass Spectrometry
chemical_list: D015415:Biomarkers; D002070:Butadienes; D002273:Carcinogens; D018736:DNA Adducts; C031763:1,3-butadiene