Smital T, Kurelec B
Department for Environmental Research, Ruder Bosković Institute, Zagreb, Croatia.
Mutat Res. 1998 Mar 13;399(1):43-53. doi: 10.1016/s0027-5107(97)00265-0.
Mechanism of multixenobiotic resistance (MXR), identical to multidrug resistance (MDR) in tumor cells, has been found in aquatic invertebrates. The presence of this ATP-dependent membrane P-glycoprotein (Pgp) pump was confirmed by biochemical ('binding'), molecular (immunohistochemical, Western, Northern), physiological (verapamil-sensitivity) and toxicological (modulation of toxicity) methods. The inducibility of MXR in the presence of xenobiotics and its wide taxonomic distribution suggests its role as a general biological defense mechanism that rescues organisms by pumping potentially toxic xenobiotics out of the cells. Some xenobiotics, the chemosensitizers, can inhibit this defense mechanism. The presence of these MXR-inhibitors has important implications on environmental parameters like exposure, uptake, internal dose, bioaccumulation, response, synergism and toxicity. Such MXR-inhibitors, for example, enhance the accumulation of carcinogenic aromatic amines in mussel, with subsequent enhancement in production of their mutagenic metabolites, in induction of single strand breaks in DNA, and in induction of DNA-adducts. The property to inhibit defense mechanism of organisms classifies MXR-inhibitors among top-hazardous environmental chemicals. Therefore, we measured the concentration of chemosensitizers in water concentrates or sediment extracts as their potential to modulate the accumulation of fluorescent dyes in a cell-culture of NIH 3T3 mouse fibroblasts stable transfected with human MDR1 gene, or as the potential of native waters to decrease the efflux-rate of Rhodamine B from gills of mussels. We found significantly higher concentrations of MXR-inhibitors in samples from polluted marine sites or from polluted rivers than in samples from corresponding unpolluted sites. These concentrations were able to enhance the accumulation of fluorescent dyes or carcinogenic aromatic amines in clams, mussels, snails and sponges exposed to these xenobiotics, demonstrating the ecotoxicological relevance of MXR-inhibitors present in polluted waters.
多异种生物抗性（MXR）机制与肿瘤细胞中的多药抗性（MDR）相同，已在水生无脊椎动物中发现。通过生化（“结合”）、分子（免疫组织化学、蛋白质印迹法、Northern印迹法）、生理（维拉帕米敏感性）和毒理学（毒性调节）方法证实了这种ATP依赖性膜P-糖蛋白（Pgp）泵的存在。在存在异种生物的情况下MXR的可诱导性及其广泛的分类分布表明其作为一种一般生物防御机制的作用，即通过将潜在有毒的异种生物泵出细胞来拯救生物体。一些异种生物，即化学增敏剂，可以抑制这种防御机制。这些MXR抑制剂的存在对环境参数如暴露、摄取、体内剂量、生物累积、反应、协同作用和毒性具有重要影响。例如，此类MXR抑制剂会增强贻贝中致癌芳香胺的积累，随后增加其诱变代谢物的产生、诱导DNA单链断裂以及诱导DNA加合物。抑制生物体防御机制的特性将MXR抑制剂归类为高危险性环境化学品。因此，我们测量了水浓缩物或沉积物提取物中化学增敏剂的浓度，其作为调节稳定转染人MDR1基因的NIH 3T3小鼠成纤维细胞培养物中荧光染料积累的潜力，或者作为天然水体降低贻贝鳃中罗丹明B流出率的潜力。我们发现，来自污染海洋站点或污染河流的样品中MXR抑制剂的浓度明显高于相应未污染站点的样品。这些浓度能够增强暴露于这些异种生物的蛤、贻贝、蜗牛和海绵中荧光染料或致癌芳香胺的积累，证明了污染水体中存在的MXR抑制剂的生态毒理学相关性。
