Renal injury and repair following S-1, 2 dichlorovinyl-L-cysteine administration to mice.
S-(1,2-dichlorovinyl)-L-cysteine (DCVC), a metabolite of a common environmental contaminant, trichloroethylene, is a selective proximal tubular nephrotoxicant. The objective of our study was to examine the dose-response relationship of renal injury and repair following DCVC administration. Male Swiss-Webster mice were injected with DCVC [15, 30, or 75 mg/kg ip in distilled water (10 ml/kg)] and the extent of nephrotoxicity and tissue repair was assessed over a 14-day period. The renal injury due to the low and medium doses of DCVC peaked at 36 and 72 h after dosing, respectively, and then regressed over time due to a timely and adequate tissue repair response. At the highest dose tissue repair was inhibited, thereby causing progression of renal injury, which led to acute renal failure and death of the mice. The possibility that compromised tissue repair was a result of the extensive nephrotoxic injury attendant to the high dose of DCVC was investigated via an equinephrotoxicity study in which separate groups of mice received 40 (LD40) and 75 (LD90) mg DCVC/kg, respectively. Bioactivation-based renal proximal tubular injury measured in these two groups over a time course was identical but there was a marked difference in mortality due to an early and robust tissue repair in the first group relative to the second group. These results support the concept that quantitative evaluation of renal tissue repair in parallel with injury is useful in the assessment of the likely toxic outcome associated with exposure to nephrotoxic drugs and toxicants.
Vaidya
Vishal S
VS
Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71209, USA.
Shankar
Kartik
K
Lock
Edward A
EA
Bucci
Thomas J
TJ
Mehendale
Harihara M
HM
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004798:Enzymes / Q000097:blood; D005947:Glucose / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000401:mortality / Q000473:pathology; D007700:Kinetics; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D012038:Regeneration
D004798:Enzymes; D018809:Proliferating Cell Nuclear Antigen; C039961:S-(1,2-dichlorovinyl)cysteine; D005947:Glucose; D003545:Cysteine