Interindividual variability in acetaminophen sulfation by human fetal liver: Implications for pharmacogenetic investigations of drug-induced birth defects

Araba A. Adjei, Andrea Gaedigk, Stephen D. Simon, Richard M Weinshilboum, J. Steven Leeder

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

BACKGROUND: Acetaminophen (APAP) use in early pregnancy has been associated with the risk of gastroschisis, a rare but serious congenital defect of the abdominal wall. The purpose of this study was to characterize the variability of APAP sulfation in a panel of human fetal livers and to identify the sulfotransferases (SULT) isoform(s) responsible for catalyzing that activity. METHODS: APAP sulfation was determined in a panel of human fetal (n = 73) and postnatal (n = 18) liver cytosol preparations and correlated with the catalytic activity of various SULT isoforms as determined using prototypic substrates and specific antibodies. RESULTS: Of 10 heterologously expressed SULT isoforms examined, SULT1A1, SULT1A3/4, SULT1E1, and SULT2A1 all catalyzed the formation of APAP sulfate with Km values of 2.4, 1.5, 1.9, and 3.7 mM, respectively. Catalytic activities for these four isoforms were expressed at varying levels in human fetal liver, and APAP sulfation was positively correlated with each of the four prototypic activities. Several regression and clustering approaches revealed that SULT1A3/4 was the primary determinant of prenatal APAP sulfation but that SULT1A1 or SULT1E1 were also major contributors in subsets of samples. CONCLUSIONS: The results of this study lead to the hypothesis that genetic variation in SULT1A3/4 represents a risk factor for the development of gastroschisis in the offspring of mothers exposed to APAP early in pregnancy. Interpretation of genetic association studies conducted to test this hypothesis will be complicated by the variable contributions of other SULTs toward APAP-sulfate formation in individual subjects.

Original languageEnglish (US)
Pages (from-to)155-165
Number of pages11
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Volume82
Issue number3
DOIs
StatePublished - Mar 2008

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Pharmacogenetics
Acetaminophen
Liver
Pharmaceutical Preparations
Sulfotransferases
Protein Isoforms
Gastroschisis
Sulfates
Pregnancy
Genetic Association Studies
Abdominal Wall
Cytosol
Cluster Analysis
Antibodies

Keywords

  • Acetaminophen
  • Fetal liver
  • Sulfotransferase
  • SULT

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Interindividual variability in acetaminophen sulfation by human fetal liver : Implications for pharmacogenetic investigations of drug-induced birth defects. / Adjei, Araba A.; Gaedigk, Andrea; Simon, Stephen D.; Weinshilboum, Richard M; Leeder, J. Steven.

In: Birth Defects Research Part A - Clinical and Molecular Teratology, Vol. 82, No. 3, 03.2008, p. 155-165.

Research output: Contribution to journalArticle

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abstract = "BACKGROUND: Acetaminophen (APAP) use in early pregnancy has been associated with the risk of gastroschisis, a rare but serious congenital defect of the abdominal wall. The purpose of this study was to characterize the variability of APAP sulfation in a panel of human fetal livers and to identify the sulfotransferases (SULT) isoform(s) responsible for catalyzing that activity. METHODS: APAP sulfation was determined in a panel of human fetal (n = 73) and postnatal (n = 18) liver cytosol preparations and correlated with the catalytic activity of various SULT isoforms as determined using prototypic substrates and specific antibodies. RESULTS: Of 10 heterologously expressed SULT isoforms examined, SULT1A1, SULT1A3/4, SULT1E1, and SULT2A1 all catalyzed the formation of APAP sulfate with Km values of 2.4, 1.5, 1.9, and 3.7 mM, respectively. Catalytic activities for these four isoforms were expressed at varying levels in human fetal liver, and APAP sulfation was positively correlated with each of the four prototypic activities. Several regression and clustering approaches revealed that SULT1A3/4 was the primary determinant of prenatal APAP sulfation but that SULT1A1 or SULT1E1 were also major contributors in subsets of samples. CONCLUSIONS: The results of this study lead to the hypothesis that genetic variation in SULT1A3/4 represents a risk factor for the development of gastroschisis in the offspring of mothers exposed to APAP early in pregnancy. Interpretation of genetic association studies conducted to test this hypothesis will be complicated by the variable contributions of other SULTs toward APAP-sulfate formation in individual subjects.",
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N2 - BACKGROUND: Acetaminophen (APAP) use in early pregnancy has been associated with the risk of gastroschisis, a rare but serious congenital defect of the abdominal wall. The purpose of this study was to characterize the variability of APAP sulfation in a panel of human fetal livers and to identify the sulfotransferases (SULT) isoform(s) responsible for catalyzing that activity. METHODS: APAP sulfation was determined in a panel of human fetal (n = 73) and postnatal (n = 18) liver cytosol preparations and correlated with the catalytic activity of various SULT isoforms as determined using prototypic substrates and specific antibodies. RESULTS: Of 10 heterologously expressed SULT isoforms examined, SULT1A1, SULT1A3/4, SULT1E1, and SULT2A1 all catalyzed the formation of APAP sulfate with Km values of 2.4, 1.5, 1.9, and 3.7 mM, respectively. Catalytic activities for these four isoforms were expressed at varying levels in human fetal liver, and APAP sulfation was positively correlated with each of the four prototypic activities. Several regression and clustering approaches revealed that SULT1A3/4 was the primary determinant of prenatal APAP sulfation but that SULT1A1 or SULT1E1 were also major contributors in subsets of samples. CONCLUSIONS: The results of this study lead to the hypothesis that genetic variation in SULT1A3/4 represents a risk factor for the development of gastroschisis in the offspring of mothers exposed to APAP early in pregnancy. Interpretation of genetic association studies conducted to test this hypothesis will be complicated by the variable contributions of other SULTs toward APAP-sulfate formation in individual subjects.

AB - BACKGROUND: Acetaminophen (APAP) use in early pregnancy has been associated with the risk of gastroschisis, a rare but serious congenital defect of the abdominal wall. The purpose of this study was to characterize the variability of APAP sulfation in a panel of human fetal livers and to identify the sulfotransferases (SULT) isoform(s) responsible for catalyzing that activity. METHODS: APAP sulfation was determined in a panel of human fetal (n = 73) and postnatal (n = 18) liver cytosol preparations and correlated with the catalytic activity of various SULT isoforms as determined using prototypic substrates and specific antibodies. RESULTS: Of 10 heterologously expressed SULT isoforms examined, SULT1A1, SULT1A3/4, SULT1E1, and SULT2A1 all catalyzed the formation of APAP sulfate with Km values of 2.4, 1.5, 1.9, and 3.7 mM, respectively. Catalytic activities for these four isoforms were expressed at varying levels in human fetal liver, and APAP sulfation was positively correlated with each of the four prototypic activities. Several regression and clustering approaches revealed that SULT1A3/4 was the primary determinant of prenatal APAP sulfation but that SULT1A1 or SULT1E1 were also major contributors in subsets of samples. CONCLUSIONS: The results of this study lead to the hypothesis that genetic variation in SULT1A3/4 represents a risk factor for the development of gastroschisis in the offspring of mothers exposed to APAP early in pregnancy. Interpretation of genetic association studies conducted to test this hypothesis will be complicated by the variable contributions of other SULTs toward APAP-sulfate formation in individual subjects.

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