MITOCHONDRIAL HSP60 (P1 PROTEIN) AND A HSP70-LIKE PROTEIN (MORTALIN) ARE MAJOR TARGETS FOR MODIFICATION DURING S-(1,1,2,2-TETRAFLUOROETHYL)-L-CYSTEINE-INDUCED NEPHROTOXICITY

The potent and site-selective nephrotoxicity of S-(1,1,2,2-tetrafluoro ethyl)-L-cysteine (TFEC) in vivo has been associated with difluorothio amidyl-L-lysine formation on critical mitochondrial target proteins. D ose-response studies in the Fischer 344 rat indicate that five protein s with apparent molecular masses of 99, 84, 66, 52, and 48 kDa are pre dominantly adducted in vivo after nephrotoxic doses of TFEC (>10 mg/kg , intraperitoneally). Microsequence analysis of the major difluorothio amidyl-L-lysine proteins indicated that P66 is identical, over 14 NH2- terminal residues, to mitochondrial P1 protein (HSP60, a chaperonin) a nd that P84 is identical, over 14 residues, to a recently isolated nov el member of the HSP70 family known as mortalin. These studies indicat e that mitochondrial heat shock proteins are major targets for modific ation by reactive metabolites of TFEC. The implications of these data in relation to the nephrotoxicity of cysteine conjugates are discussed .