CLONAL ADAPTATION OF CANCER-CELLS IN FLATFISH LIVER TO ENVIRONMENTAL CONTAMINATION BY CHANGES IN EXPRESSION OFF P-GP RELATED MXR, CYP450, GST-A AND G6PDH ACTIVITY

Progression from eosinophilic foci to persistent basophilic foci and c arcinomas was observed in pollution-induced hepatocellular carcinogene sis in European flounder (Platichthys flesus L.) in a similar sequence as in chemically induced liver cancer in mammals. Image analysis was used to quantify enzyme activity and protein expression as visualised by enzyme and immunohistochemistry in various stages of toxipathic les ions and carcinogenesis. In eosinophilic foci, growth advantage was ac hieved by increased production of NADPH and pentoses for biosynthesis and cell proliferation due to increased G6PDN capacity during the fir sr steps of clonal adaptation. Simultaneously, oxyradical production b y CYP450, phase I was reduced. Overexpression of P-gp mediating multi- xenobiotic resistance was noted in basophilic cell types which persist ed during progression towards carcinomas. This was accompanied by incr eased protein levels of oxyradical scavenging GST-A. These changes are consistent with adaptation and phenotypic expression of the multidrug or xenobiotic resistance (MDR/MXR) type in hepatocarcinomas of Europe an flounder. (C) 1998 Elsevier Science Ltd. All rights reserved.