Immunohistochemically demonstrated suppressed expression of tryptophan oxygenase, a marker for liver differentiation, within putative preneoplastic rat liver lesions

The behaviour of rat liver putative preneoplastic lesions withrespect to the enzyme tryptophan oxygenase (TO), a liver-specificdifferentiation marker, and a possible growth-related marker,glucose-6-phosphate dehydrogenase (G6PD) was investigated duringand after their induction by diethylnitros-amine initiationand subsequent ‘selection pressure’. Using specificantibodies to rat liver TO and G6PD and the avidin-biotin complexmethod for immunohistochemical staining it was demonstratedthat all of the nodular lesions showing increased expressionof G6PD during the induction phase were also negative or deficientin TO enzyme protein. With the onset of ‘phenotypic instability’or loss of marker enzymes, a gradual return to normal expressionof TO activity was evident. Administration of dexamethasoneand L-tryptophan 11 weeks after cessation of carcinogen treatmentallowed differentiation between morphologically altered, apparentlypersisting lesions in which no, or little, enzyme inductionwas apparent and instable lesions showing a strong increasein levels of TO protein. Thus, persisting nodular lesions sharea common lack of response to normal homeostatic physiologicalcontrol.