title: Subchronic chloroform priming protects mice from a subsequently administered lethal dose of chloroform.
abstract: Protection offered by pre-exposure priming with a small dose of a toxicant against the toxic and lethal effects of a subsequently administered high dose of the same toxicant is autoprotection. Although autoprotection has been extensively studied with diverse toxicants in acute exposure regimen, not much is known about autoprotection after priming with repeated exposure. The objective of this study was to investigate this concept following repeated exposure to a common water contaminant, chloroform. Swiss Webster (SW) mice, exposed continuously to either vehicle (5% Emulphor, unprimed) or chloroform (150 mg/kg/day po, primed) for 30 days, were challenged with a normally lethal dose of chloroform (750 mg chloroform/kg po) 24 h after the last exposure. As expected, 90% of the unprimed mice died between 48 and 96 h after administration of the lethal dose in contrast to 100% survival of mice primed with chloroform. Time course studies indicated lower hepato- and nephrotoxicity in primed mice as compared to unprimed mice. Hepatic CYP2E1, glutathione levels (GSH), and covalent binding of (14)C-chloroform-derived radiolabel did not differ between livers of unprimed and primed mice after lethal dose exposure, indicating that protection in liver is neither due to decreased bioactivation nor increased detoxification. Kidney GSH and glutathione reductase activity were upregulated, with a concomitant reduction in oxidized glutathione in the primed mice following lethal dose challenge, leading to decreased renal covalent binding of (14)C-chloroform-derived radiolabel, in the absence of any change in CYP2E1 levels. Buthionine sulfoximine (BSO) intervention led to 70% mortality in primed mice challenged with lethal dose. These data suggest that higher detoxification may play a role in the lower initiation of kidney injury observed in primed mice. Exposure of primed mice to a lethal dose of chloroform led to 40% lower chloroform levels (AUC(15-360 min)) in the systemic circulation. Exhalation of (14)C-chloroform was unchanged in primed as compared to unprimed mice (AUC(1-6 h)). Urinary excretion of (14)C-chloroform was higher in primed mice after administration of the lethal dose. However, neither slightly higher urinary elimination nor unchanged expiration can account for the difference in systemic levels of chloroform. Liver and kidney regeneration was inhibited by the lethal dose in unprimed mice leading to progressive injury, organ failure, and 90% mortality. In contrast, sustained and highly stimulated compensatory hepato- and nephrogenic repair prevented the progression of injury resulting in 100% survival of primed mice challenged with the lethal dose. These findings affirm the critical role of tissue regeneration and favorable detoxification (only in kidney) of the lethal dose of chloroform in subchronic chloroform priming-induced autoprotection.
authors.affiliation: Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71209-0495, USA.
authors.forename: Binu K
authors.initials: BK
authors.lastname: Philip
authors.forename: Sathanandam S
authors.initials: SS
authors.lastname: Anand
authors.forename: Prajakta S
authors.initials: PS
authors.lastname: Palkar
authors.forename: Moiz M
authors.initials: MM
authors.lastname: Mumtaz
authors.forename: John R
authors.initials: JR
authors.lastname: Latendresse
authors.forename: Harihara M
authors.initials: HM
authors.lastname: Mehendale
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D019328:Buthionine Sulfoximine / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury; D002725:Chloroform / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007441:Intubation, Gastrointestinal; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D008107:Liver Diseases / Q000401:mortality / Q000517:prevention & control*; D051379:Mice; D015996:Survival Rate
chemical_list: D019328:Buthionine Sulfoximine; D002725:Chloroform; D019392:Cytochrome P-450 CYP2E1; D005980:Glutathione Reductase; D000410:Alanine Transaminase; D005978:Glutathione