Reduction of Hepatotoxicity Induced by Acetaminophen Overdoses in a Mouse Model of Inflammation Induced by Freund´s Adjuvants

Noel Perez Garcia

doi:10.4172/2155-6121.1000183

Abstract

Acetaminophen (APAP) is often used as an analgesic and antipyretic during the inflammatory process. Its toxicity in overdoses depends on the integrity of the hepatic cytochrome P450 (CYP). The oxidative drug metabolism mediated by CYP can be inhibited during inflammatory diseases or after use of immuno-stimulants drugs and vaccines. The objective of this work was to evaluate if inflammation is able to modulate the toxicity of APAP. Five female Balb/c mice were injected subcutaneously with Freund Complete Adjuvant (FCA), and boosted with Freund’s Incomplete Adjuvant (FIA) at 14th day. Then, they were treated with 360 mg/kg of acetaminophen orally during the 14th, 15th and 16th days. Convenient control groups were included with APAP administration without immuno-stimulation. Serum levels of IL-1β, TNFα, IFNγ, α-1-acid glycoprotein (α-1-AGP), alanine transaminase (ALT), aspartic acid aminotransferase (AST), lactate dehydrogenase (LDH) and hepatic CYP2E1 expression were measured. Inoculation site of adjuvants and liver histopathological responses were also evaluated. FCA/FIA injection produced acute inflammatory response in the inoculation site and increased serum levels of the pro-inflammatory cytokines, α-1-AGP and LDH with reduction of hepatic CYP2E1 expression. A reduction of liver damage induced by APAP overdoses was also observed, suggesting that inflammatory processes can be protective against APAP hepatotoxicity.

Highlights

It has been documented that when host defense mechanisms are stimulated, there is a concomitant decrease in different hepatic cytochrome P450 enzymes (CYP), with impact in the drug biotransformation and elimination
Analyzing the enzymatic level in the treated groups, it was noted that a significant increment of alanine transaminase (ALT) and AST in the APAP-treated group as evidence of hepatotoxicity induced by the overdose
It is interesting that in the group with co-administration of Freund’s Adjuvants (FA) the levels of both enzymes were lower than positive control treated with APAP alone, indicating a hepatoprotective effect provoked by the inflammation (Figure 3)

Summary

Introduction

It has been documented that when host defense mechanisms are stimulated, there is a concomitant decrease in different hepatic cytochrome P450 enzymes (CYP), with impact in the drug biotransformation and elimination. This has resulted in a number of clinically important unwanted drug responses in patients with infections or inflammatory responses [1]. Acetaminophen (N-acetyl-p-aminophenol) (APAP), referred to as paracetamol, is one of the common analgesics and antipyretic drugs It is generally considered harmless at therapeutic doses, but in overdose causes severe and sometimes fatal hepatic damage in humans and experimental animals [5,6]. In overdoses the production of NAPQI increases producing severe hepatic damage [6] (Figure 1)

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