Urinary bile acid profile of newborns born by cesarean section is characterized by oxidative metabolism of primary bile acids: Limited roles of fetal-specific CYP3A7 in cholate oxidations

Wen Xia Wang, Li Chen, Guo Yu Wang, Jin Ling Zhang, Xian Wen Tan, Qiu Hong Lin, Yu Jie Chen, Jian Zhang, Ping Ping Zhu, Jia Miao, Ming Ming Su, Chang Xiao Liu, Wei JIA, Ke Lan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

This work aims to investigate how the bile acid metabolism of newborns differs from that of adults along the axis of primary, secondary, and tertiary bile acids (BAs). The total unconjugated BA profiles were quantitatively determined by enzyme digestion techniques in urine of 21 newborns born by cesarean section, 29 healthy parturient women, 30 healthy males, and 28 healthy nonpregnant females. As expected, because of a lack of developed gutmicrobiota, newborns exhibited poormetabolism of secondary BAs. Accordingly, the tertiary BAs contributed limitedly to the urinary excretion of BAs in newborns despite their tertiary-tosecondary ratios significantly increasing. As a result, the primary BAs of newborns underwent extensive oxidative metabolism, resulting in elevated urinary levels of some fetal-specific BAs, including 3-dehydroCA, 3β,7α,12α-trihydroxy-5β-cholan-24-oic acid, 3α,12-oxo-hydroxy-5β-cholan-24-oic acid, and nine tetrahydroxy-cholan-24-oic acids (Tetra-BAs). Parturient women had significantly elevated urinary levels of tertiary BAs and fetalspecific BAs compared with female control, indicating that they may be excreted into amniotic fluid for maternal disposition. An in vitro metabolism assay in infant liver microsomes showed that four Tetra-BAs and 3-dehydroCA were hydroxylated metabolites of cholate, glycocholate, and particularly taurocholate. However, the recombinant cytochrome P450 enzyme assay found that the fetalspecific CYP3A7 did not contribute to these oxidationmetabolisms as much as expected compared with CYP3A4. In conclusion, newborns show a BA metabolism pattern predominated by primary BA oxidations due to immaturity of secondary BA metabolism. Translational studies following this finding may bring new ideas and strategies for both pediatric pharmacology and diagnosis and treatment of perinatal cholestasis-associated diseases.

Original languageEnglish
Pages (from-to)662-672
Number of pages11
JournalDrug Metabolism and Disposition
Volume48
Issue number8
DOIs
Publication statusPublished - 1 Aug 2020

Scopus Subject Areas

  • Pharmacology
  • Pharmaceutical Science

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