Interindividual variability in acetaminophen sulfation by human fetal liver: implications for pharmacogenetic investigations of drug-induced birth defects.
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Adjei AA, Gaedigk A, Simon SD, Weinshilboum RM, Leeder JS
Interindividual variability in acetaminophen sulfation by human fetal liver: implications for pharmacogenetic investigations of drug-induced birth defects.
Birth Defects Res A Clin Mol Teratol. 2008 Mar;82(3):155-65. doi: 10.1002/bdra.20535.
- PubMed ID
- 18232020 [ View in PubMed]
- 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 K(m) 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Acetaminophen Sulfotransferase 1A1 Protein Humans UnknownSubstrateDetails Acetaminophen Sulfotransferase 1A3/1A4 Protein Humans UnknownSubstrateDetails Propacetamol Bile salt sulfotransferase Protein Humans NoSubstrateDetails Propacetamol Estrogen sulfotransferase Protein Humans NoSubstrateDetails Propacetamol Sulfotransferase 1A1 Protein Humans NoSubstrateDetails Propacetamol Sulfotransferase 1A3/1A4 Protein Humans NoSubstrateDetails