SPECIES-DIFFERENCES IN THE GLUTATHIONE TRANSFERASE GSTT1-1 ACTIVITY TOWARDS THE MODEL SUBSTRATES METHYL-CHLORIDE AND DICHLOROMETHANE IN LIVER AND KIDNEY

Glutathione transferase (GST) GSTT1-1 is involved in the biotransforma tion of several chemicals widely used in industry, such as butadiene a nd dichloro methane DCM. The polymorphic hGSTT1-1 may well play a role in the development of kidney rumours after high and long-term occupat ional exposure against trichloroethylene. Although several studies hav e investigated the association of this polymorphism with malignant dis eases little is known about its enzyme activity in potential extrahepa tic target tissues, The known theta-specific substrates methyl chlorid e (MC) dichloromethane and 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) were used to assay GSTT1-1 activity in liver and kidney of rats, mice, hamsters and humans differentiating the three phenotypes (non-conjuga tors, low conjugators, high conjugators) seen in humans. In addition G STT1-1 activity towards MC and DCM was determined in human erythrocyte s. No GSTT1-1 activity was found in any tissue of non-conjugators (NC) . In all organs high conjugators (HC) showed twofold higher activity t owards MC and DCM than low conjugators (LC). The activity in human sam ples towards EPNP was too close to the detection limit to differentiat e between the three conjugator phenotypes. GSTT1-1 activity towards MC was two to seven-times higher in liver cytosol than in kidney cytosol . The relation for MC between species was identical in both organs: mo use > HC > rat > LC > hamster > NC. In rats, mice and hamsters GSTT1-1 activity in liver cytosol towards DCM was also two to seven-times hig her than in the kidney cytosol. In humans this activity was twice as h igh in kidney cytosol than in liver cytosol. The relation between spec ies was mouse > rat > HC > LC > hamster > NC for liver, but mouse > HC > LC/ rat > hamster/NC for kidney cytosol, The importance to heed the specific environment at potential target sites in risk assessment is emphasized by these results.