Glutathione transferase activities in renal carcinomas and adjacent normalrenal tissues: factors influencing renal carcinogenesis induced by xenobiotics

In general, the biological activation of nephrocarcinogenic chlorinated hyd rocarbons proceeds via conjugation with glutathione. It has mostly been ass umed that the main site of initial conjugation is the liver, followed by a mandatory transfer of intermediates to the kidney. It was therefore of inte rest to study the enzyme activities of subgroups of glutathione transferase s (GSTs) in renal cancers and the surrounding normal renal tissues of the s ame individuals (n = 21). For genotyping the individuals with respect to kn own polymorphic GST isozymes the following substrates with differential spe cificity were used: 1-chloro-2,4-dinitrobenzene for overall GST activity (e xcept GST theta); 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole for GST alpha; 1, 2-dichloro-4-nitro-benzene for GST mu; ethacrynic acid and 4-vinylpyridine for GST pi; and methyl chloride for GST theta. In general, the normal tissu es were able to metabolize the test substrates. A general decrease in indiv idual GST enzyme activities was apparent in the course of cancerization, an d in some (exceptional) cases individual activities, expressed in the norma l renal tissue, were lost in the tumour tissue. The GST enzyme activities i n tumours were independent of tumour stage, or the age and gender of the pa tients. There was little influence of known polymorphisms of GSTM1, GSTM3 a nd GSTP1 upon the activities towards the test substrates, whereas the influ ence of GSTT1 polymorphism on the activity towards methyl chloride was stra ightforward. In general, the present findings support the concept that the initial GST-dependent bioactivation step of nephrocarcinogenic chlorinated hydrocarbons may take place in the kidney itself. This should be a consider ation in toxicokinetic modelling.