AstraZeneca, Safety Health and Environment, Brixham Environmental Laboratory, Freshwater Quarry, Brixham, Devon, TQ5 8BA, UK.
Environ Toxicol. 2012 Oct;27(10):573-82. doi: 10.1002/tox.20684. Epub 2011 Mar 7.
The conservation of common physiological systems across vertebrate classes suggests the potential for certain pharmaceuticals, which have been detected in surface waters, to produce biological effects in nontarget vertebrates such as fish. However, previous studies assessing the effects of such compounds in fish have not taken into account the potential for metabolism and elimination. This study aimed to assess if propranolol, a β-adrenergic receptor antagonist or β-blocker, could modulate EROD activity (indicative of CYP1A activity) in rainbow trout (Oncorhynchus mykiss) gills and liver. For this, an in vivo time course exposure with 1 mg/L was conducted. Additionally, using measured in vivo plasma concentrations, an in vitro exposure at human therapeutic levels was undertaken. This allowed comparison of in vitro and in vivo rates of EROD activity, thus investigating the applicability of cell preparations as surrogates for whole animal enzyme activity analysis. In vitro exposure of suspended liver and gill cells at concentrations similar to in vivo levels resulted in EROD activity in both tissues, but with significantly higher rates (up to six times in vivo levels). These results show that propranolol exposure elevated EROD activity in the liver and gill of rainbow trout, and that this is demonstrable both in vivo (albeit nonsignificantly in the liver) and in vitro, thus supporting the use of the latter as a surrogate of the former. These data also provide an insight into the potential role of the gill as a site of metabolism of pharmaceuticals in trout, suggesting that propranolol (and feasibly other pharmaceuticals) may undergo "first pass" metabolism in this organ.
脊椎动物类群中常见生理系统的保守性表明,某些已在地表水中检测到的药物有可能对鱼类等非靶标脊椎动物产生生物效应。然而,先前评估此类化合物对鱼类影响的研究并未考虑到代谢和消除的可能性。本研究旨在评估普萘洛尔(一种β-肾上腺素能受体拮抗剂或β-阻断剂)是否能调节虹鳟鱼(Oncorhynchus mykiss)鳃和肝脏中的 EROD 活性(指示 CYP1A 活性)。为此,进行了 1mg/L 的体内时间过程暴露。此外,还在人治疗水平下进行了测量的体内血浆浓度的体外暴露。这允许比较体外和体内 EROD 活性的速率,从而研究细胞制剂作为替代整体动物酶活性分析的适用性。在与体内水平相似的浓度下对悬浮肝脏和鳃细胞进行体外暴露会导致这两种组织中的 EROD 活性,但速率显著更高(体内水平的六倍)。这些结果表明,普萘洛尔暴露会提高虹鳟鱼肝脏和鳃中的 EROD 活性,并且这在体内(尽管在肝脏中无显著性)和体外都可以证明,因此支持后者作为前者的替代物。这些数据还深入了解了鳃作为鱼类中药物代谢的潜在部位的作用,表明普萘洛尔(和可能其他药物)可能在该器官中经历“首过”代谢。