The Hamner Institutes for Health Sciences, RTP, NC 27709, United States.
Toxicol In Vitro. 2013 Aug;27(5):1451-7. doi: 10.1016/j.tiv.2013.03.012. Epub 2013 Mar 29.
Species and organ differences in the intrinsic clearance and the enzymes involved in the metabolism of DEHP were examined in subcellular fractions of the intestine and liver as well as by recombinant cytochrome P450 (CYP) isoforms of human and rat. Estimated clearance (CLint) of DEHP via esterase-mediated pathway in human intestine was 2.4-fold greater than that in human liver while its value in rat intestine was 1.7-fold less than that in rat liver. Ranks of CLint for CYP-mediated oxidation/dealkylation of MEHP were human liver>rat liver>human intestine>rat intestine. Estimates of CLint for the production of mono(2-ethyl-5-hydroxyhexyl) phthalate and mono(2-ethyl-5-oxohexyl) phthalate by human CYP2C9 1 were 4.2- and 2.6-fold greater than those by rat CYP2C6, respectively. Total CLint via hCYP2C9 3-mediated oxidation was 1.9- and 2.6-fold less than those by hCYP2C9 2 and 2C9 1, respectively. Estimated CLint for phthalic acid production by hCYP3A4 was 24.5 μL nmol CYP(-1)min(-1) while it was continuously produced by rCYP2C6 and 3A2 via passive mechanism. These species/organ differences in major metabolic pathway and CYP isoforms should be considered for appraisal of the potential adverse health effects of DEHP.
研究了 DEHP 代谢中涉及的固有清除率和酶在肠道和肝脏的亚细胞部分以及人源和鼠源重组细胞色素 P450（CYP）同工酶中的种属和器官差异。通过人源肠酯酶介导途径估计的 DEHP 清除率（CLint）是人源肝脏的 2.4 倍，而鼠源肠中的值是人源肝脏的 1.7 倍。CYP 介导的 MEHP 氧化/脱烷基化的 CLint 排名为人源肝脏>鼠源肝脏>人源肠>鼠源肠。人源 CYP2C9 1 产生单（2-乙基-5-羟基己基）邻苯二甲酸酯和单（2-乙基-5-氧代己基）邻苯二甲酸酯的 CLint 估计值分别比鼠源 CYP2C6 高 4.2 倍和 2.6 倍。hCYP2C9 3 介导的氧化的总 CLint 分别比 hCYP2C9 2 和 2C9 1 低 1.9 倍和 2.6 倍。hCYP3A4 生产邻苯二甲酸的 CLint 估计值为 24.5 μL nmol CYP(-1)min(-1)，而 rCYP2C6 和 3A2 则通过被动机制持续产生邻苯二甲酸。在评估 DEHP 的潜在不良健康影响时，应考虑主要代谢途径和 CYP 同工酶的这些种属/器官差异。
