TY - JOUR
T1 - Urinary bile acid profile of newborns born by cesarean section is characterized by oxidative metabolism of primary bile acids
T2 - Limited roles of fetal-specific CYP3A7 in cholate oxidations
AU - Wang, Wen Xia
AU - Chen, Li
AU - Wang, Guo Yu
AU - Zhang, Jin Ling
AU - Tan, Xian Wen
AU - Lin, Qiu Hong
AU - Chen, Yu Jie
AU - Zhang, Jian
AU - Zhu, Ping Ping
AU - Miao, Jia
AU - Su, Ming Ming
AU - Liu, Chang Xiao
AU - JIA, Wei
AU - Lan, Ke
N1 - Funding Information:
This work was supported partly by the Fundamental Research Funds for the Central Universities and the 111 Project of the National Ministry of Education (B18035). 1W.-X.W. and L.C. contributed equally to this work. https://doi.org/10.1124/dmd.120.000011. s This article has supplemental material available at dmd.aspetjournals.org.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85088237951&partnerID=8YFLogxK
U2 - 10.1124/DMD.120.000011
DO - 10.1124/DMD.120.000011
M3 - Journal article
C2 - 32499339
AN - SCOPUS:85088237951
SN - 0090-9556
VL - 48
SP - 662
EP - 672
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 8
ER -