Investigation of Hepatoprotection Afforded by Repeated Exposure to Acetaminophen

Details

• Personal Author:
  Benson RW ; Black M ; Ho LL ; Ma X ; Roberts, Daryl W. ; Shayiq R ; Snawder, John E.
• Description:
  Acetaminophen (A) toxicity is associated with its biotransformation to N-acetyl-p-benzoquinone imine, which, after glutathione is depleted, binds to protein thiols as 3-(cystein-S-yl)A-protein adduct (3-Cys-A). Previously, we reported remarkable resistance to supra-toxic doses of A (up to 65 g/day) in a physician who ingested progressively more A in codeine- and A-containing tablets as a consequence of Petcocet addiction. To emulate this, mice were pretreated for eight days with increasing doses of A (A-pretreated). Controls received saline (S-pretreated). S-Pretreated mice challenged with 500 or 1000 mg/kg A on day 9 developed typical hepatotoxicity and the higher dose was lethal. In contrast, A-pretreated mice were protected as evidenced by an almost 400% increase in LD50. A-Pretreatment resulted in a >40% decrease in hepatic P450, decreased CYP2El activity, and> 40% decreases in microsomal CYP2El and CYPIA2. Immunohistochemical staining for 3-Cys-A revealed an atypical distribution of A-protein adducts. Staining for PCNA revealed normal cell proliferative activity in S-pretreated animals, but increased proliferative activity as a consequence of A-pretreatment. Collectively, the data indicate that the association between covalent binding and toxicity may become uncoupled in A tolerance; that the mechanism of protection involves both inactivation of P450 and an ongoing cell proliferative response (autoprotection); and that the assessment of toxicity following repeated or chronic A exposure must consider parameters besides those used to assess acute A overdose. [Description provided by NIOSH]
• Subjects:
  Animals Environmental Monitoring Hazardous Substances Laboratories Liver Occupational Exposure Occupational Health Safety
• Keywords:
  Animal-studies Cell-morphology Cell-transformation Chronic-exposure Chronic-toxicity Exposure-assessment Hepatotoxicity Laboratory-animals Liver-cells Liver-disorders
• ISSN:
  0731-9193
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Arkansas ; Ohio ; OSHA Region 3 ; OSHA Region 5 ; OSHA Region 6 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  DBBS - Division of Biomedical and Behavioral Sciences
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  15
• Issue:
  1
• NIOSHTIC Number:
  nn:20032265
• Citation:
  Toxicologist 1995 Mar; 15(1):151
• CAS Registry Number:
  Glutathione (CAS RN 70-18-8)
• Federal Fiscal Year:
  1995
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 34th Annual Meeting, March 5-9,1995, Baltimore, Maryland
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:c7c9a40a54e4aa06d3e3c8cbf7e1a124b5a6327a9641ab46d2cbe6378b066afb90946316fab0e7caac0c67bf707f1d1fbc00b55e2589a6b57184a9ec6dc81626
• Download URL:
  https://stacks.cdc.gov/view/cdc/186296/cdc_186296_DS1.pdf
• File Type:
  [PDF - 889.78 KB ]