High throughput HPLC-ESI--MS/MS methodology for mercapturic acid metabolites of 1,3-butadiene: Biomarkers of exposure and bioactivation

Srikanth Kotapati; Amanda Esades; Brock Matter; Chap Le; Natalia Tretyakova

doi:10.1016/j.cbi.2015.02.009

High throughput HPLC-ESI^--MS/MS methodology for mercapturic acid metabolites of 1,3-butadiene: Biomarkers of exposure and bioactivation

Srikanth Kotapati, Amanda Esades, Brock Matter, Chap Le, Natalia Tretyakova

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

1,3-Butadiene (BD) is an important industrial and environmental carcinogen present in cigarette smoke, automobile exhaust, and urban air. The major urinary metabolites of BD in humans are 2-(N-acetyl-l-cystein-S-yl)-1-hydroxybut-3-ene/1-(N-acetyl-l-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA), 4-(N-acetyl-l-cystein-S-yl)-1,2-dihydroxybutane (DHBMA), and 4-(N-acetyl-l-cystein-S-yl)-1,2,3-trihydroxybutyl mercapturic acid (THBMA), which are formed from the electrophilic metabolites of BD, 3,4-epoxy-1-butene (EB), hydroxymethyl vinyl ketone (HMVK), and 3,4-epoxy-1,2-diol (EBD), respectively. In the present work, a sensitive high-throughput HPLC-ESI^--MS/MS method was developed for simultaneous quantification of MHBMA and DHBMA in small volumes of human urine (200 μl). The method employs a 96 well Oasis HLB SPE enrichment step, followed by isotope dilution HPLC-ESI^--MS/MS analysis on a triple quadrupole mass spectrometer. The validated method was used to quantify MHBMA and DHBMA in urine of workers from a BD monomer and styrene-butadiene rubber production facility (40 controls and 32 occupationally exposed to BD). Urinary THBMA concentrations were also determined in the same samples. The concentrations of all three BD-mercapturic acids and the metabolic ratio (MHBMA/(MHBMA + DHBMA + THBMA)) were significantly higher in the occupationally exposed group as compared to controls and correlated with BD exposure, with each other, and with BD-hemoglobin biomarkers. This improved high throughput methodology for MHBMA and DHBMA will be useful for future epidemiological studies in smokers and occupationally exposed workers.

Original language	English (US)
Pages (from-to)	23-31
Number of pages	9
Journal	Chemico-Biological Interactions
Volume	241
DOIs	https://doi.org/10.1016/j.cbi.2015.02.009
State	Published - Nov 5 2015

Bibliographical note

Funding Information:
We thank Cullin Bachmeier, Chromtech and Gerald Nagatani, Phenomenex for providing technical assistance on SPE method development and HPLC column selection. We are also thankful to Gregory Janis (Medtox Laboratories) and Steve Carmella (University of Minnesota Cancer Center) for their helpful advice during method development and Robert Carlson for preparing graphics for this paper. SK was partially supported by a doctoral dissertation fellowship from the University of Minnesota Graduate School. All the mass spectrometry work in this paper was performed at the Analytical Biochemistry facility at the Masonic Cancer Center, University of Minnesota. This research was supported by grants from the NCI ( CA-138338 ) and the American Chemistry Council Olefins Panel . Urine samples from occupationally exposed workers were generously provided by Professor Richard J. Albertini (University of Vermont) and the repository maintained by the American Chemistry Council Olefins Panel.

Publisher Copyright:
© 2015 Elsevier Ireland Ltd.

Keywords

1 3-Butadiene
Metabolism
Occupational exposure
Quantitative analysis
Urinary metabolites

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title = "High throughput HPLC-ESI--MS/MS methodology for mercapturic acid metabolites of 1,3-butadiene: Biomarkers of exposure and bioactivation",

abstract = "1,3-Butadiene (BD) is an important industrial and environmental carcinogen present in cigarette smoke, automobile exhaust, and urban air. The major urinary metabolites of BD in humans are 2-(N-acetyl-l-cystein-S-yl)-1-hydroxybut-3-ene/1-(N-acetyl-l-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA), 4-(N-acetyl-l-cystein-S-yl)-1,2-dihydroxybutane (DHBMA), and 4-(N-acetyl-l-cystein-S-yl)-1,2,3-trihydroxybutyl mercapturic acid (THBMA), which are formed from the electrophilic metabolites of BD, 3,4-epoxy-1-butene (EB), hydroxymethyl vinyl ketone (HMVK), and 3,4-epoxy-1,2-diol (EBD), respectively. In the present work, a sensitive high-throughput HPLC-ESI--MS/MS method was developed for simultaneous quantification of MHBMA and DHBMA in small volumes of human urine (200 μl). The method employs a 96 well Oasis HLB SPE enrichment step, followed by isotope dilution HPLC-ESI--MS/MS analysis on a triple quadrupole mass spectrometer. The validated method was used to quantify MHBMA and DHBMA in urine of workers from a BD monomer and styrene-butadiene rubber production facility (40 controls and 32 occupationally exposed to BD). Urinary THBMA concentrations were also determined in the same samples. The concentrations of all three BD-mercapturic acids and the metabolic ratio (MHBMA/(MHBMA + DHBMA + THBMA)) were significantly higher in the occupationally exposed group as compared to controls and correlated with BD exposure, with each other, and with BD-hemoglobin biomarkers. This improved high throughput methodology for MHBMA and DHBMA will be useful for future epidemiological studies in smokers and occupationally exposed workers.",

keywords = "1 3-Butadiene, Metabolism, Occupational exposure, Quantitative analysis, Urinary metabolites",

author = "Srikanth Kotapati and Amanda Esades and Brock Matter and Chap Le and Natalia Tretyakova",

note = "Funding Information: We thank Cullin Bachmeier, Chromtech and Gerald Nagatani, Phenomenex for providing technical assistance on SPE method development and HPLC column selection. We are also thankful to Gregory Janis (Medtox Laboratories) and Steve Carmella (University of Minnesota Cancer Center) for their helpful advice during method development and Robert Carlson for preparing graphics for this paper. SK was partially supported by a doctoral dissertation fellowship from the University of Minnesota Graduate School. All the mass spectrometry work in this paper was performed at the Analytical Biochemistry facility at the Masonic Cancer Center, University of Minnesota. This research was supported by grants from the NCI ( CA-138338 ) and the American Chemistry Council Olefins Panel . Urine samples from occupationally exposed workers were generously provided by Professor Richard J. Albertini (University of Vermont) and the repository maintained by the American Chemistry Council Olefins Panel. Publisher Copyright: {\textcopyright} 2015 Elsevier Ireland Ltd.",

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doi = "10.1016/j.cbi.2015.02.009",

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T1 - High throughput HPLC-ESI--MS/MS methodology for mercapturic acid metabolites of 1,3-butadiene

T2 - Biomarkers of exposure and bioactivation

AU - Kotapati, Srikanth

AU - Esades, Amanda

AU - Matter, Brock

AU - Le, Chap

AU - Tretyakova, Natalia

N1 - Funding Information: We thank Cullin Bachmeier, Chromtech and Gerald Nagatani, Phenomenex for providing technical assistance on SPE method development and HPLC column selection. We are also thankful to Gregory Janis (Medtox Laboratories) and Steve Carmella (University of Minnesota Cancer Center) for their helpful advice during method development and Robert Carlson for preparing graphics for this paper. SK was partially supported by a doctoral dissertation fellowship from the University of Minnesota Graduate School. All the mass spectrometry work in this paper was performed at the Analytical Biochemistry facility at the Masonic Cancer Center, University of Minnesota. This research was supported by grants from the NCI ( CA-138338 ) and the American Chemistry Council Olefins Panel . Urine samples from occupationally exposed workers were generously provided by Professor Richard J. Albertini (University of Vermont) and the repository maintained by the American Chemistry Council Olefins Panel. Publisher Copyright: © 2015 Elsevier Ireland Ltd.

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N2 - 1,3-Butadiene (BD) is an important industrial and environmental carcinogen present in cigarette smoke, automobile exhaust, and urban air. The major urinary metabolites of BD in humans are 2-(N-acetyl-l-cystein-S-yl)-1-hydroxybut-3-ene/1-(N-acetyl-l-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA), 4-(N-acetyl-l-cystein-S-yl)-1,2-dihydroxybutane (DHBMA), and 4-(N-acetyl-l-cystein-S-yl)-1,2,3-trihydroxybutyl mercapturic acid (THBMA), which are formed from the electrophilic metabolites of BD, 3,4-epoxy-1-butene (EB), hydroxymethyl vinyl ketone (HMVK), and 3,4-epoxy-1,2-diol (EBD), respectively. In the present work, a sensitive high-throughput HPLC-ESI--MS/MS method was developed for simultaneous quantification of MHBMA and DHBMA in small volumes of human urine (200 μl). The method employs a 96 well Oasis HLB SPE enrichment step, followed by isotope dilution HPLC-ESI--MS/MS analysis on a triple quadrupole mass spectrometer. The validated method was used to quantify MHBMA and DHBMA in urine of workers from a BD monomer and styrene-butadiene rubber production facility (40 controls and 32 occupationally exposed to BD). Urinary THBMA concentrations were also determined in the same samples. The concentrations of all three BD-mercapturic acids and the metabolic ratio (MHBMA/(MHBMA + DHBMA + THBMA)) were significantly higher in the occupationally exposed group as compared to controls and correlated with BD exposure, with each other, and with BD-hemoglobin biomarkers. This improved high throughput methodology for MHBMA and DHBMA will be useful for future epidemiological studies in smokers and occupationally exposed workers.

AB - 1,3-Butadiene (BD) is an important industrial and environmental carcinogen present in cigarette smoke, automobile exhaust, and urban air. The major urinary metabolites of BD in humans are 2-(N-acetyl-l-cystein-S-yl)-1-hydroxybut-3-ene/1-(N-acetyl-l-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA), 4-(N-acetyl-l-cystein-S-yl)-1,2-dihydroxybutane (DHBMA), and 4-(N-acetyl-l-cystein-S-yl)-1,2,3-trihydroxybutyl mercapturic acid (THBMA), which are formed from the electrophilic metabolites of BD, 3,4-epoxy-1-butene (EB), hydroxymethyl vinyl ketone (HMVK), and 3,4-epoxy-1,2-diol (EBD), respectively. In the present work, a sensitive high-throughput HPLC-ESI--MS/MS method was developed for simultaneous quantification of MHBMA and DHBMA in small volumes of human urine (200 μl). The method employs a 96 well Oasis HLB SPE enrichment step, followed by isotope dilution HPLC-ESI--MS/MS analysis on a triple quadrupole mass spectrometer. The validated method was used to quantify MHBMA and DHBMA in urine of workers from a BD monomer and styrene-butadiene rubber production facility (40 controls and 32 occupationally exposed to BD). Urinary THBMA concentrations were also determined in the same samples. The concentrations of all three BD-mercapturic acids and the metabolic ratio (MHBMA/(MHBMA + DHBMA + THBMA)) were significantly higher in the occupationally exposed group as compared to controls and correlated with BD exposure, with each other, and with BD-hemoglobin biomarkers. This improved high throughput methodology for MHBMA and DHBMA will be useful for future epidemiological studies in smokers and occupationally exposed workers.

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KW - Occupational exposure

KW - Quantitative analysis

KW - Urinary metabolites

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