Differential cellular effects in the toxicity of haloalkene and haloalkane cysteine conjugates to rabbit renal proximal tubules.
The relationship between the covalent binding, uptake, and toxicity produced by S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC) was investigated in suspensions of rabbit renal proximal tubules (RPT). The DCVC and TFEC at concentrations of 25 microM produced a time-dependent (1-6 hours) loss of RPT viability. The TFEC was biotransformed rapidly by beta-lyase to a reactive metabolite which bound covalently to tubular protein. Approximately 63% of the TFEC-equivalents inside the cell were bound to protein. Covalent binding of TFEC-equivalents was associated with a 30% decrease in tubular basal and state 3 respiration, a sevenfold increase in lipid peroxidation, and, ultimately, cell death. The DCVC was biotransformed rapidly to a reactive metabolite which bound covalently to tubular protein. Approximately 90% of the DCVC-equivalents inside the cell were bound covalently to tubular protein. Following exposure to 25 microM DCVC, the binding of DCVC-equivalents was associated with a 17-fold increase in lipid peroxidation but, in contrast to TFEC, had no effect on tubular respiration. However, exposure of RPT to 100 microM DCVC resulted in a ninefold increase in the binding of DCVC-equivalents and a 30% decrease in tubular state 3 respiration. The beta-lyase inhibitor aminooxyacetic acid (AOAA) blocked the covalent binding, mitochondrial dysfunction, lipid peroxidation, and cell death produced by TFEC. The AOAA decreased the covalent binding and the lipid peroxidation produced by DCVC by approximately 60-70% but had no effect on cell death.(ABSTRACT TRUNCATED AT 250 WORDS)
Groves
C E
CE
Department of Physiology, College of Medicine, University of Arizona, Tucson 85724.
Hayden
P J
PJ
Lock
E A
EA
Schnellmann
R G
RG
D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D016923:Cell Death / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D006845:Hydrocarbons, Fluorinated / Q000493:pharmacokinetics / Q000633:toxicity; D006846:Hydrocarbons, Halogenated / Q000493:pharmacokinetics / Q000633:toxicity*; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011817:Rabbits; D013462:Sulfur Radioisotopes; D005466:Fluorocarbons
D000625:Aminooxyacetic Acid; D003545:Cysteine; D006845:Hydrocarbons, Fluorinated; D006846:Hydrocarbons, Halogenated; D013462:Sulfur Radioisotopes; C039961:S-(1,2-dichlorovinyl)cysteine; C064116:S-(1,1,2,2-tetrafluoroethyl)cysteine; D005466:Fluorocarbons