Clonal adaptation of cancer cells in flatfish liver to environmental contamination by changes in expression of P-gp related MXR, CYP450, GST-A and G6PDH activity

Progression from eosinophilic foci to persistent basophilic foci and carcinomas was observed in pollution-induced hepatocellular carcinogenesis 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 lesions and carcinogenesis. In eosinophilic foci, growth advantage was achieved by increased production of NADPH and pentoses for biosynthesis and cell proliferation due to increased G6PDH capacity during the first steps of clonal adaptation. Simultaneously, oxyradical production by CYP450, phase I was reduced. Overexpression of P-gp mediating multi-xenobiotic resistance was noted in basophilic cell types which persisted during progression towards carcinomas. This was accompanied by increased 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 European flounder.