Abstract
Prolonged unconjugated hyperbilirubinemia in infants associated with breast milk feeding is a common pediatric problem known as breast milk jaundice (BMJ). A polymorphic mutation (G71R) of bilirubin UDP-glucuronosyltransferase (UGT1A1) is a known cause of BMJ on the infantile side, but the responsible components of breast milk are not currently known. We analyzed the inhibitory effect of 5β-pregnane-3α,20β-diol (pregnanediol) on transcriptional activity and enzyme activity of UGT1A1. To this end, we constructed two types of expression vectors. One type comprised vectors including the upstream enhancer-promoter sequence of UGT1A1 for WT and variant type (-3279T>G with A(TA)7TAA), used in studying transcriptional regulation. The other type comprised vectors including cDNA of UGT1A1 for WT and the G71R variant, used in studying enzyme activity. In an in vitro expression study, pregnanediol did not affect the transcriptional activity of UGT1A1 enhancer-promoter complex of WT and variant type, even with coexistence of transcriptional factors such as constitutive androstane receptor or pregnane X receptor. In contrast, in the presence of 100 μM pregnanediol, bilirubin glucuronidation of G71R-UGT1A1 was reduced to 51% of WT. We suggest that pregnanediol is a cause of breast milk jaundice in carriers of G71R.
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Abbreviations
- BMJ:
-
breast milk jaundice
- CAR:
-
constitutive androstane receptor
- MEM:
-
minimal essential medium
- PXR:
-
pregnane X receptor
- UGT1A1:
-
bilirubin UDP-glucuronosyltransferase
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We thank M. Suzaki of the Central Research Laboratory, Shiga University of Medical Science for technical assistance.
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Ota, Y., Maruo, Y., Matsui, K. et al. Inhibitory Effect of 5β-Pregnane-3α,20β-Diol on Transcriptional Activity and Enzyme Activity of Human Bilirubin UDP-Glucuronosyltransferase. Pediatr Res 70, 453–457 (2011). https://doi.org/10.1203/PDR.0b013e31822f242e
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DOI: https://doi.org/10.1203/PDR.0b013e31822f242e
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