Investigation of hepatoprotection afforded by repeated exposure to acetaminophen.
Roberts-DW; Shayiq-R; Snawder-JE; Benson-RW; Ho-LL; Ma-X; Black-M
Toxicologist 1995 Mar; 15(1):151
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.
Exposure-assessment; Cell-morphology; Cell-transformation; Animal-studies; Laboratory-animals; Chronic-exposure; Chronic-toxicity; Hepatotoxicity; Liver-cells; Liver-disorders
The Toxicologist. Society of Toxicology 34th Annual Meeting, March 5-9,1995, Baltimore, Maryland