Erickson D A, Goodrich M S, Lech J J
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226.
Toxicol Appl Pharmacol. 1988 Jun 15;94(1):1-10. doi: 10.1016/0041-008x(88)90331-6.
Although piperonyl butoxide (PBO) is commonly used both in vivo and in vitro as an inhibitor of cytochrome P-450-dependent monooxygenase (MO) activity in a wide variety of species, the effect of PBO on the hepatic MO of fishes has never been characterized. The MO activity in hepatic microsomes from rainbow trout exposed to either 1 or 2 ppm PBO for 24 hr in a static system was induced to a similar level in both treatment groups. Conversely, when PBO was administered in a flow-through system to trout, the hepatic microsomes of treated animals contained MO activities that were induced in a dose-dependent manner. Furthermore, total cytochrome P-450 was significantly increased in the livers of trout treated in a flow-through system with 1 ppm or more of PBO. The in vitro inhibition kinetics of PBO toward the 7-ethoxycoumarin-O-deethylase (ECOD) and 7-ethoxyresorufin-O-deethylase (EROD) activities of hepatic microsomes from trout treated with beta-naphthoflavone (BNF) (100 mg/kg, ip) or PBO (4 ppm by flow-through) and untreated trout were compared with Dixon plots. With respect to ECOD activity, the slopes of Dixon plots from control, BNF- and PBO-treated animals were similar. However, the slopes of Dixon plots of EROD inhibition by PBO in microsomes from BNF- and PBO-treated trout were significantly different from each other. Treatment of trout with PBO in a flow-through system resulted in an increase in ECOD and EROD activity in hepatic microsomes while simultaneously decreasing their activity toward [14C]rotenone oxidation. These data suggest that the cytochrome P-450 isozyme composition in hepatic microsomes from PBO-treated rainbow trout may be qualitatively different from that of BNF-treated trout. Also, the activity of hepatic microsomes from PBO-treated trout toward a specific substrate may be either inhibited or induced.
尽管胡椒基丁醚（PBO）在体内和体外都普遍用作多种物种中细胞色素P-450依赖性单加氧酶（MO）活性的抑制剂，但PBO对鱼类肝脏MO的影响尚未得到表征。在静态系统中，将虹鳟鱼暴露于1或2 ppm的PBO中24小时，两个处理组肝脏微粒体中的MO活性均被诱导至相似水平。相反，当在流通系统中给鳟鱼施用PBO时，处理过的动物的肝脏微粒体中MO活性呈剂量依赖性诱导。此外，在流通系统中用1 ppm或更高浓度的PBO处理的鳟鱼肝脏中，总细胞色素P-450显著增加。用Dixon图比较了PBO对用β-萘黄酮（BNF）（100 mg/kg，腹腔注射）或PBO（通过流通方式为4 ppm）处理的鳟鱼以及未处理鳟鱼肝脏微粒体的7-乙氧基香豆素-O-脱乙基酶（ECOD）和7-乙氧基试卤灵-O-脱乙基酶（EROD）活性的体外抑制动力学。关于ECOD活性，来自对照、BNF处理和PBO处理动物的Dixon图斜率相似。然而，PBO对BNF处理和PBO处理的鳟鱼微粒体中EROD抑制的Dixon图斜率彼此显著不同。在流通系统中用PBO处理鳟鱼导致肝脏微粒体中ECOD和EROD活性增加，同时降低其对[14C]鱼藤酮氧化的活性。这些数据表明，用PBO处理的虹鳟鱼肝脏微粒体中的细胞色素P-450同工酶组成在性质上可能与用BNF处理的鳟鱼不同。此外，用PBO处理的鳟鱼肝脏微粒体对特定底物的活性可能被抑制或诱导。
