School of Agriculture, Sun Yat-sen University, Guangzhou 510275, China; Guangdong Provincial Key Laboratory of Emergency Test for Dangerous Chemicals, China National Analytical Center Guangzhou (Guangdong Institute of Analysis), Guangdong Academy of Sciences, 100 Xianlie Middle Road, Guangzhou 510070, China.
School of Agriculture, Sun Yat-sen University, Guangzhou 510275, China.
Sci Total Environ. 2021 May 10;768:144430. doi: 10.1016/j.scitotenv.2020.144430. Epub 2021 Jan 4.
Although hepatic metabolism of hexabromocyclododecanes (HBCDs) played critical roles in the selective bioaccumulation of HBCDs in humans, the hepatic metabolism patterns of its enantiomers remained ambiguous. Aiming to elucidate the mechanism on hepatic metabolism of hexabromocyclododecanes (HBCDs) enantiomers, the enantiomers ((+)-α-HBCD, (-)-α-HBCD, (+)-γ-HBCD, and (-)-γ-HBCD), the diastereoisomers (α-, β-, and γ-HBCDs) and the mixed of α- and γ-HBCDs were incubated with human HepG2 cell under different exposure levels in the present study. The clearance percentages ranked as γ-HBCD enantiomers >β-HBCD enantiomers >α-HBCD enantiomers at the same exposure levels. The clearance percentages of (+)- and (-)-α-HBCDs increased when cells were exposed to racemic α-HBCD and the mixture of racemic α- and γ-HBCDs (p < 0.05). (-)-γ-HBCD was more resistant to human hepatic metabolism than (+)-γ-HBCD, leading to the enantiomer fractions (EFs) of γ-HBCD lower than 0.50. (-)-α-HBCD was slightly more metabolized when independently exposed to α-HBCD, while (+)-α-HBCD was more preferentially metabolized after exposure to α- and γ-HBCD mixtures. Hydroxylation and debromination HBCD metabolites were identified. In addition, the different EFs of HBCDs in cells and mediums suggested the selective transfer of chiral HBCDs and HBCD metabolites through the cell membrane. This study provided new insight into the enantiomer-selective metabolism of HBCDs.
尽管六溴环十二烷（HBCDs）的肝脏代谢在 HBCDs 在人体中的选择性生物累积中起着关键作用，但 HBCDs 对映体的肝脏代谢模式仍不清楚。本研究旨在阐明六溴环十二烷（HBCDs）对映体的肝脏代谢机制，将对映体（(+) - α-HBCD、(-) - α-HBCD、(+) - γ-HBCD 和 (-) - γ-HBCD）、非对映异构体（α-、β-和γ-HBCDs）和α-和γ-HBCDs 的混合物与 HepG2 细胞在不同暴露水平下孵育。在相同暴露水平下，清除率百分比依次为γ-HBCD 对映体>β-HBCD 对映体>α-HBCD 对映体。当细胞暴露于外消旋α-HBCD 和外消旋α-和γ-HBCD 混合物时，(+) - 和 (-) - α-HBCD 的清除率百分比增加（p < 0.05）。(-) - γ-HBCD 比 (+) - γ-HBCD 更能抵抗人体肝脏代谢，导致γ-HBCD 的对映体分数（EF）低于 0.50。当单独暴露于α-HBCD 时，(-) - α-HBCD 被稍微更多地代谢，而当暴露于α-和γ-HBCD 混合物时，(+) - α-HBCD 被更优先代谢。鉴定了羟基化和脱溴 HBCD 代谢物。此外，细胞和培养基中 HBCDs 的不同 EF 表明手性 HBCDs 和 HBCD 代谢物通过细胞膜选择性转移。本研究为 HBCDs 的对映体选择性代谢提供了新的见解。
