Bis-butanediol-mercapturic acid (bis-BDMA) as a urinary biomarker of metabolic activation of butadiene to its ultimate carcinogenic species

Srikanth Kotapati, Dewakar Sangaraju, Amanda Esades, Lance Hallberg, Vernon E. Walker, James A. Swenberg, Natalia Y. Tretyakova

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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-(Nacetyl- 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.

Original languageEnglish (US)
Pages (from-to)1371-1378
Number of pages8
Issue number6
StatePublished - Jun 2014

Bibliographical note

Funding Information:
National Cancer Institute (CA-138338). Animal exposures were covered by a grant from the National Institute of Environmental Health Sciences (ES012689-05, sub-award 5-51624). The mass spectrometry analyses were performed at the Analytical Biochemistry Facility Core of the University of Minnesota Masonic Cancer Center, which is supported in part by grant CA-77598 from the U.S. National Cancer Institute. S.K. was partially supported by a doctoral dissertation fellowship from the University of Minnesota Graduate School.

Publisher Copyright:
© The Author 2014. Published by Oxford University Press. All rights reserved.

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