Impact of repeated exposure on toxicity of perchloroethylene in Swiss Webster mice.
The aim was to study the subchronic toxicity of perchloroethylene (Perc) by measuring injury and repair in liver and kidney in relation to disposition of Perc and its major metabolites. Male SW mice (25-29g) were given three dose levels of Perc (150, 500, and 1000 mg/kg day) via aqueous gavage for 30 days. Tissue injury was measured during the dosing regimen (0, 1, 7, 14, and 30 days) and over a time course of 24-96h after the last dose (30 days). Perc produced significant liver injury (ALT) after single day exposure to all three doses. Liver injury was mild to moderate and regressed following repeated exposure for 30 days. Subchronic Perc exposure induced neither kidney injury nor dysfunction during the entire time course as evidenced by normal renal histology and BUN. TCA was the major metabolite detected in blood, liver, and kidney. Traces of DCA were also detected in blood at initial time points after single day exposure. With single day exposure, metabolism of Perc to TCA was saturated with all three doses. AUC/dose ratio for TCA was significantly decreased with a concomitant increase in AUC/dose of Perc levels in liver and kidney after 30 days as compared to 1 day exposures, indicating inhibition of metabolism upon repeated exposure to Perc. Hepatic CYP2E1 expression and activity were unchanged indicating that CYP2E1 is not the critical enzyme inhibited. Hepatic CYP4A expression, measured as a marker of peroxisome proliferation was increased transiently only on day 7 with the high dose, but was unchanged at later time points. Liver tissue repair peaked at 7 days, with all three doses and was sustained after medium and high dose exposure for 14 days. These data indicate that subchronic Perc exposure via aqueous gavage does not induce nephrotoxicity and sustained hepatotoxicity suggesting adaptive hepatic repair mechanisms. Enzymes other than CYP2E1, involved in the metabolism of Perc may play a critical role in the metabolism of Perc upon subchronic exposure in SW mice. Liver injury decreased during repeated exposure due to inhibition of metabolism and possibly due to adaptive tissue repair mechanisms.
Philip
Binu K
BK
Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71209, USA.
Mumtaz
Moiz M
MM
Latendresse
John R
JR
Mehendale
Harihara M
HM
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001806:Blood Urea Nitrogen; D056486:Chemical and Drug Induced Liver Injury; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D004261:DNA Replication / Q000502:physiology; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D006651:Histocytochemistry; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D013750:Tetrachloroethylene / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D013936:Thymidine / Q000378:metabolism; D014238:Trichloroacetic Acid / Q000378:metabolism
D004785:Environmental Pollutants; D018809:Proliferating Cell Nuclear Antigen; D014238:Trichloroacetic Acid; D019392:Cytochrome P-450 CYP2E1; D042926:Cytochrome P-450 CYP4A; D000410:Alanine Transaminase; D005978:Glutathione; D013750:Tetrachloroethylene; D013936:Thymidine