Padrós Jaime, Pelletier Emilien, Ribeiro Ciro Oliveira
Institut des sciences de la mer de Rimouski, Université du Québec à Rimouski, 310 allée des Ursulines, Rimouski, Québec, Canada G5L 3A1.
Toxicol Appl Pharmacol. 2003 Oct 1;192(1):45-55. doi: 10.1016/s0041-008x(02)00042-x.
We have previously reported that short-term, single exposure to a high dose of tributyltin (TBT), a widely used antifouling biocide, inhibited both the in vivo metabolism and metabolic activation of the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP) in fish; (BaP), in turn, stimulated TBT metabolism. Here, we provide further mechanistic evidence of mutual metabolic interactions between BaP and TBT in response to long-term, repeated exposures to low doses. Juvenile Arctic charr (Salvelinus alpinus) received 10 separate i.p. injections (a single injection every 6 days) of BaP (3 mg/kg), TBT (0.3 mg/kg), or both in combination; control fish received corn oil vehicle only. Two days after the 2nd (Day 8), 6th (Day 32), and 10th dose (Day 56), blood, bile, and liver samples were collected and analyzed for a suite of biomarkers. HPLC/fluorescence analysis indicated that TBT cotreatment inhibited the formation of (+)-anti-BaP diol-epoxide adducts with plasma albumin (53%, Day 8), hepatic DNA (27%, Day 32), or both albumin and globin (50 and 58%, Day 56) compared to BaP alone. This antagonistic interaction was associated with a time-dependent modulation (inhibition at Day 8, enhancement at Day 32) of both cytochrome P450 (P450)1A-mediated ethoxyresorufin O-deethylase (EROD) activity and biliary BaP metabolite formation. TBT cotreatment also inhibited (39%) the BaP-mediated induction of hepatic glutathione S-transferase (GST) activity observed at Day 8. Treatment with TBT alone increased EROD activity (60%) at Day 32, but decreased both GST activity (70 and 37%) and glutathione content (24% and 16%) at Days 32 and 56, respectively. GC/MS analysis revealed that, at Day 56, BaP cotreatment increased (200%) the levels of biliary butyltin compounds, including mono- and dibutyltin metabolites. This potentiative interaction was associated with a protective effect of BaP cotreatment against the TBT-mediated decreases in GST activity and glutathione content. The current results demonstrate that, whereas TBT inhibited BaP bioactivation via a time-dependent modulation of P4501A induction, BaP stimulated the Phase II metabolism of TBT and/or its biliary excretion. The mutual metabolic interactions between these two widespread aquatic pollutants reinforce the need for long-term in vivo interactive studies at low doses.
我们之前曾报道，短期单次暴露于高剂量的三丁基锡（TBT）（一种广泛使用的防污杀生剂）会抑制鱼类体内致癌性多环芳烃苯并[a]芘（BaP）的代谢及代谢活化；反过来，BaP会刺激TBT的代谢。在此，我们提供了进一步的机制证据，证明在长期重复低剂量暴露情况下，BaP与TBT之间存在相互代谢作用。幼年北极红点鲑（Salvelinus alpinus）接受10次单独的腹腔注射（每6天注射一次），分别注射BaP（3 mg/kg）、TBT（0.3 mg/kg）或两者的组合；对照鱼仅接受玉米油赋形剂。在第2次（第8天）、第6次（第32天）和第10次给药（第56天）后的两天，采集血液、胆汁和肝脏样本，并分析一系列生物标志物。高效液相色谱/荧光分析表明，与单独使用BaP相比，TBT联合处理抑制了血浆白蛋白（第8天，53%）、肝脏DNA（第32天，27%）或白蛋白和球蛋白两者（第56天，50%和58%）与（+）-反式-BaP二醇环氧化物加合物的形成。这种拮抗作用与细胞色素P450（P450）1A介导的乙氧基异吩唑酮O-脱乙基酶（EROD）活性和胆汁BaP代谢物形成的时间依赖性调节（第8天抑制，第32天增强）有关。TBT联合处理还抑制了第8天观察到的BaP介导的肝脏谷胱甘肽S-转移酶（GST）活性诱导（39%）。单独使用TBT处理在第32天增加了EROD活性（60%），但在第32天和第56天分别降低了GST活性（70%和37%）和谷胱甘肽含量（24%和16%）。气相色谱/质谱分析显示，在第56天，BaP联合处理使胆汁丁基锡化合物（包括单丁基锡和二丁基锡代谢物）的水平增加了（200%）。这种增效作用与BaP联合处理对TBT介导的GST活性和谷胱甘肽含量降低的保护作用有关。当前结果表明，虽然TBT通过对P4501A诱导的时间依赖性调节抑制BaP生物活化，但BaP刺激了TBT的II相代谢和/或其胆汁排泄。这两种广泛存在的水生污染物之间的相互代谢作用强化了进行低剂量长期体内相互作用研究的必要性。
