McMaster University, Department of Biology, Hamilton, ON, Canada L8S 4K1.
Chemosphere. 2010 Mar;79(1):26-32. doi: 10.1016/j.chemosphere.2010.01.058. Epub 2010 Feb 19.
Pharmaceuticals discharged in municipal wastewater are of emerging concern because of their potential for inducing biological effects in aquatic organisms. Selective serotonin reuptake inhibitors (SSRIs), pharmaceuticals prescribed to treat chronic depression, have been detected in receiving and wastewaters. Fluoxetine is a highly prescribed model SSRI used to assess impacts of antidepressants on aquatic organisms. In this study, in vitro hepaticfluoxetine metabolism was determined in several model fish species: rainbow trout, goldfish, zebrafish and killifish. Incubation of fluoxetine with hepatic microsomes from trout pre-treated with carbamazepine showed a time-dependant loss of fluoxetine, concomitant with an increase in norfluoxetine, the major mammalian demethylated metabolite. However, fluoxetine was not well metabolized in reactions with hepatic microsomes from untreated fish. Fluoxetine loss was greater than norfluoxetine production, indicating that norfluoxetine is not the predominant fluoxetine biotransformation product in fish. Furthermore, norfluoxetine was often undetected, possibly indicating that fluoxetine demethylation is a minor metabolic pathway in fish. Inter-species differences in fluoxetine metabolism were not evident because of high intra-species variability, although killifish appeared to have the highest hepatic metabolic capacity for fluoxetine. Fluoxetine metabolism in mammals is catalyzed by cytochrome P450 (CYP) enzymes. Trout were exposed to knownCYP inducers, carbamazepine and 3-methylcholanthrene, to assess potential induction of hepatic fluoxetine metabolism. Microsomes from 3-methylcholanthrene treated fish did not induce detectable changes in fluoxetine concentrations in vitro, indicating that fish CYP1s are not involved in fluoxetine metabolism; the CYPs involved are still unclear. Identification of metabolites other than norfluoxetine warrants further investigation.
排入城市废水中的药物引起了人们的关注，因为它们可能对水生生物产生生物效应。选择性 5-羟色胺再摄取抑制剂（SSRIs）是用于治疗慢性抑郁症的药物，已在接收和废水中检测到。氟西汀是一种高处方的 SSRI，用于评估抗抑郁药对水生生物的影响。在这项研究中，在几种模式鱼类中确定了氟西汀的体外肝代谢：虹鳟鱼、金鱼、斑马鱼和食蚊鱼。用卡马西平预处理的虹鳟鱼肝微粒体孵育氟西汀表明，氟西汀随时间的推移而减少，同时伴随着去甲氟西汀的增加，去甲氟西汀是哺乳动物主要的脱甲基代谢产物。然而，未处理的鱼肝微粒体与氟西汀的反应并不能很好地代谢氟西汀。氟西汀的损失大于去甲氟西汀的产生，表明去甲氟西汀不是鱼类中氟西汀的主要生物转化产物。此外，由于鱼类中去甲氟西汀的含量通常较低，因此去甲氟西汀的含量往往无法检测到，这可能表明氟西汀的脱甲基作用是鱼类中的一种次要代谢途径。由于种内变异性较大，因此没有明显的种间差异，尽管食蚊鱼似乎具有最高的肝对氟西汀的代谢能力。哺乳动物中氟西汀的代谢是由细胞色素 P450（CYP）酶催化的。向虹鳟鱼暴露于已知的 CYP 诱导剂，如卡马西平和 3-甲基胆蒽，以评估对肝氟西汀代谢的潜在诱导作用。用 3-甲基胆蒽处理的微粒体在体外没有诱导可检测到的氟西汀浓度变化，表明鱼类 CYP1 不参与氟西汀代谢；涉及的 CYP 仍不清楚。需要进一步研究以确定除去甲氟西汀以外的代谢物。
