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-tetrafluoroethyl)-L-cysteine (TFEC) in vivo has been associated with difluorothioamidyl-L-lysine formation on critical mitochondrial target proteins. Dose-response studies in the Fischer 344 rat indicate that five proteins with apparent molecular masses of 99, 84, 66, 52, and 48 kDa are predominantly adducted in vivo after nephrotoxic doses of TFEC (> 10 mg/kg, intraperitoneally). Microsequence analysis of the major difluorothioamidyl-L-lysine proteins indicated that P66 is identical, over 14 NH2-terminal residues, to mitochondrial P1 protein (HSP60, a chaperonin) and that P84 is identical, over 14 residues, to a recently isolated novel member of the HSP70 family known as mortalin. These studies indicate that mitochondrial heat shock proteins are major targets for modification by reactive metabolites of TFEC. The implications of these data in relation to the nephrotoxicity of cysteine conjugates are discussed.
Bruschi
S A
SA
W. Alton Jones Cell Science Center, Lake Placid, New York 12946.
West
K A
KA
Crabb
J W
JW
Gupta
R S
RS
Stevens
J L
JL
D000595:Amino Acid Sequence; D000818:Animals; D001219:Aspartate Aminotransferases / Q000737:chemistry; D018833:Chaperonins; D003545:Cysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000737:chemistry*; D006845:Hydrocarbons, Fluorinated / Q000633:toxicity*; D007668:Kidney / Q000737:chemistry / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects; D008969:Molecular Sequence Data; D011233:Precipitin Tests; D011506:Proteins / Q000737:chemistry*; D051381:Rats; D011916:Rats, Inbred F344; D005466:Fluorocarbons
D001219:Aspartate Aminotransferases; D018833:Chaperonins; D003545:Cysteine; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006845:Hydrocarbons, Fluorinated; D011506:Proteins; C080352:mortalin; C064116:S-(1,1,2,2-tetrafluoroethyl)cysteine; D005466:Fluorocarbons