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

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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.

Original languageEnglish (US)
Pages (from-to)1371-1378
Number of pages8
JournalCarcinogenesis
Volume35
Issue number6
DOIs
StatePublished - 2014

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Butylene Glycols
Acetylcysteine
Biomarkers
Urine
1,3-butadiene
Metabolic Activation
DNA Adducts
Electrospray Ionization Mass Spectrometry
Tandem Mass Spectrometry
Isotopes
Carcinogens
Inhalation
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Cancer Research

Cite this

Kotapati, S., Sangaraju, D., Esades, A., Hallberg, L., Walker, V. E., Swenberg, J. A., & Tretyakova, N. Y. (2014). Bis-butanediol-mercapturic acid (bis-BDMA) as a urinary biomarker of metabolic activation of butadiene to its ultimate carcinogenic species. Carcinogenesis, 35(6), 1371-1378. https://doi.org/10.1093/carcin/bgu047

Bis-butanediol-mercapturic acid (bis-BDMA) as a urinary biomarker of metabolic activation of butadiene to its ultimate carcinogenic species. / Kotapati, Srikanth; Sangaraju, Dewakar; Esades, Amanda; Hallberg, Lance; Walker, Vernon E.; Swenberg, James A.; Tretyakova, Natalia Y.

In: Carcinogenesis, Vol. 35, No. 6, 2014, p. 1371-1378.

Research output: Contribution to journalArticle

Kotapati, S, Sangaraju, D, Esades, A, Hallberg, L, Walker, VE, Swenberg, JA & Tretyakova, NY 2014, 'Bis-butanediol-mercapturic acid (bis-BDMA) as a urinary biomarker of metabolic activation of butadiene to its ultimate carcinogenic species.', Carcinogenesis, vol. 35, no. 6, pp. 1371-1378. https://doi.org/10.1093/carcin/bgu047
Kotapati, Srikanth ; Sangaraju, Dewakar ; Esades, Amanda ; Hallberg, Lance ; Walker, Vernon E. ; Swenberg, James A. ; Tretyakova, Natalia Y. / Bis-butanediol-mercapturic acid (bis-BDMA) as a urinary biomarker of metabolic activation of butadiene to its ultimate carcinogenic species. In: Carcinogenesis. 2014 ; Vol. 35, No. 6. pp. 1371-1378.
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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.",
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