Smith Jordan N, Mehinagic Denis, Nag Subhasree, Crowell Susan R, Corley Richard A
Pacific Northwest National Laboratory, Richland, WA 99352, USA.
Pacific Northwest National Laboratory, Richland, WA 99352, USA.
Toxicol Lett. 2017 Mar 5;269:23-32. doi: 10.1016/j.toxlet.2017.01.008. Epub 2017 Jan 21.
Polycyclic aromatic hydrocarbons (PAHs) are contaminants that are ubiquitously found in the environment, produced through combustion of organic matter or petrochemicals, and many of which are procarcinogens. The prototypic PAH, benzo[a]pyrene (B[a]P) and the highly carcinogenic dibenzo[def,p]chrysene (DBC) are metabolically activated by isoforms of the P450 enzyme superfamily producing benzo[a]pyrene-7,8-dihydrodiol (B[a]P diol), dibenzo[def,p]chrysene-11,12 diol (DBC diol). Each of these diols can be further metabolized by cytochrome P450 enzymes to highly reactive diol-epoxide metabolites that readily react with DNA or by phase II conjugation facilitating excretion. To complement prior in vitro metabolism studies with parent B[a]P and DBC, both phase I metabolism and phase II glucuronidation of B[a]P diol and DBC diol were measured in hepatic microsomes from female B6129SF1/J mice, male Sprague-Dawley rats, and female humans. Metabolic parameters, including intrinsic clearance and Michaelis-Menten kinetics were calculated from substrate depletion data. Mice and rats demonstrated similar B[a]P diol phase I metabolic rates. Compared to rodents, human phase I metabolism of B[a]P diol demonstrated lower overall metabolic capacity, lower intrinsic clearance at higher substrate concentrations (>0.14μM), and higher intrinsic clearance at lower substrate concentrations (<0.07μM). Rates of DBC diol metabolism did not saturate in mice or humans and were highest overall in mice. Higher affinity constants and lower capacities were observed for DBC diol glucuronidation compared to B[a]P diol glucuronidation; however, intrinsic clearance values for these compounds were consistent within each species. Kinetic parameters reported here will be used to extend physiologically based pharmacokinetic (PBPK) models to include the disposition of B[a]P and DBC metabolites in animal models and humans to support future human health risk assessments.
多环芳烃（PAHs）是环境中普遍存在的污染物，通过有机物或石化产品燃烧产生，其中许多是前致癌物。典型的多环芳烃苯并[a]芘（B[a]P）和高致癌性的二苯并[def,p]芘（DBC）通过细胞色素P450酶超家族的同工型进行代谢活化，生成苯并[a]芘-7,8-二氢二醇（B[a]P二醇）、二苯并[def,p]芘-11,12二醇（DBC二醇）。这些二醇中的每一种都可以被细胞色素P450酶进一步代谢为极易与DNA反应的高反应性二醇环氧化物代谢物，或者通过II相共轭促进排泄。为补充先前对母体B[a]P和DBC的体外代谢研究，对雌性B6129SF1/J小鼠、雄性Sprague-Dawley大鼠和女性人类肝脏微粒体中B[a]P二醇和DBC二醇的I相代谢及II相葡萄糖醛酸化进行了测定。根据底物消耗数据计算代谢参数，包括内在清除率和米氏动力学参数。小鼠和大鼠的B[a]P二醇I相代谢率相似。与啮齿动物相比，人类B[a]P二醇的I相代谢总体代谢能力较低，在较高底物浓度（>0.14μM）时内在清除率较低，在较低底物浓度（<0.07μM）时内在清除率较高。DBC二醇的代谢率在小鼠或人类中未达到饱和，总体上在小鼠中最高。与B[a]P二醇葡萄糖醛酸化相比，DBC二醇葡萄糖醛酸化的亲和力常数更高，能力更低；然而，这些化合物在每个物种中的内在清除率值是一致的。此处报告的动力学参数将用于扩展基于生理的药代动力学（PBPK）模型，以纳入动物模型和人类中B[a]P和DBC代谢物的处置情况，以支持未来的人类健康风险评估。
