T. Smital et B. Kurelec, THE CHEMOSENSITIZERS OF MULTIXENOBIOTIC RESISTANCE MECHANISM IN AQUATIC INVERTEBRATES - A NEW CLASS OF POLLUTANTS, Mutation research. Fundamental and molecular mechanisms of mutagenesis, 399(1), 1998, pp. 43-53
Mechanism of multixenobiotic resistance (MXR), identical to multidrug
resistance (MDR) in tumor-cells, has been found in aquatic invertebrat
es. The presence of this ATP-dependent membrane P-glycoprotein (Pgp) p
ump was confirmed by biochemical ('binding'), molecular (immunohistoch
emical, Western, Northern), physiological (verapamil-sensitivity) and
toxicological (modulation of toxicity) methods. The inducibility of MX
R in the presence of xenobiotics and its wide taxonomic distribution s
uggests its role as a general biological defense mechanism that rescue
s organisms by pumping potentially toxic xenobiotics out of the cells.
Some xenobiotics, the chemosensitizers, can inhibit this defense mech
anism. The presence of these MXR-inhibitors has important implications
on environmental parameters like exposure, uptake, internal dose, bio
accumulation, response, synergism and toxicity. Such MXR-inhibitors, f
or example, enhance the accumulation of carcinogenic aromatic amines i
n mussel, with subsequent enhancement in production of their mutagenic
metabolites, in induction of single strand breaks in DNA, and in indu
ction of DNA-adducts. The property to inhibit defense mechanism of org
anisms classifies MXR-inhibitors among top-hazardous environmental che
micals. Therefore, we measured the concentration of chemosensitizers i
n water concentrates or sediment extracts as their potential to modula
te the accumulation of fluorescent dyes in a cell-culture of NIH 3T3 m
ouse fibroblasts stable transfected with human MDR1 gene, or as the po
tential of native waters to decrease the efflux-rate of Rhodamine B fr
om gills of mussels. We found significantly higher concentrations of M
XR-inhibitors in samples from polluted marine sites or from polluted r
ivers than in samples from corresponding unpolluted sites. These conce
ntrations were able to enhance the accumulation of fluorescent dyes or
carcinogenic aromatic amines in clams, mussels, snails and sponges ex
posed to these xenobiotics, demonstrating the ecotoxicological relevan
ce of MXR-inhibitors present in polluted waters. (C) 1998 Elsevier Sci
ence B.V.