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Loss of CYP2E1 and CYP1A2 activity as a function of acetaminophen dose: relation to toxicity

J E Snawder1, A L Roe, R W Benson

  • 1Division of Biochemical Toxicology, FDA, Jefferson, AR 72079.

Biochemical and Biophysical Research Communications
|August 30, 1994
PubMed

Insights

Acetaminophen (APAP) bioactivation and toxicity depend on dose. Cytochrome P450 2E1 (CYP2E1) is key at low APAP doses, while Cytochrome P450 1A2 (CYP1A2) contributes more significantly at higher doses.

Area of Science:

  • Pharmacology
  • Toxicology
  • Biochemistry

Background:

  • Acetaminophen (APAP) overdose is a leading cause of acute liver failure.
  • Cytochrome P450 enzymes, particularly CYP2E1 and CYP1A2, are involved in APAP bioactivation.
  • The dose-dependent role of these enzymes in APAP toxicity requires further elucidation.

Purpose of the Study:

  • To investigate the effect of varying acetaminophen (APAP) doses on CYP2E1 and CYP1A2 activity.
  • To determine the contribution of CYP2E1 and CYP1A2 to APAP bioactivation and hepatotoxicity at different doses.

Main Methods:

  • Mice were pretreated with acetone to induce CYP2E1 or beta-napthaflavone to induce CYP1A2.
  • Animals received either 150 mg/kg or 400 mg/kg APAP.
  • Hepatotoxicity, enzyme activity (CYP2E1, CYP1A2), and covalent binding of APAP metabolites were assessed.

Main Results:

  • At 150 mg/kg APAP, minimal toxicity and CYP2E1 activity loss were observed in control mice.
  • 400 mg/kg APAP caused significant hepatotoxicity and reduced activity of both CYP2E1 and CYP1A2.
  • In induced mice, CYP2E1 was critical for low-dose APAP bioactivation, while CYP1A2 played a greater role at high doses.

Conclusions:

  • CYP2E1 is the primary enzyme for APAP bioactivation at lower doses.
  • CYP1A2 contributes more significantly to APAP bioactivation and subsequent toxicity at higher doses.
  • Enzyme induction significantly influences APAP-induced hepatotoxicity, highlighting the importance of dose and enzyme status.

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