University of Louisville

Poster Title

Down Regulation of CYP1A2 Expression Following Acetaminophen Exposure: Potential Implications on Adaptive Tolerance

Institution

University of Louisville

Abstract

As of 2003, acetaminophen (APAP)-induced hepatotoxicity became the leading cause of acute liver failure in the Unites States. When the major APAP metabolism route becomes saturated, hepatotoxicity results from a harmful metabolite called N-acetyl-p-benzoquinone imine (NAPQI). Cytochrome P450 1A2 (CYP1A2) and 2E1 (CYP2E1) are known to catalyze the production of NAPQI. The mechanisms leading to accidental overdose and death are not fully understood, however adaptive tolerance in mice has proven to protect them against a lethal dose. We hypothesize it is the down regulation of CYP2E1 during the period of toleration that accounts for the mice not succumbing to hepatotoxic affects of APAP. Because CYP1A2 is also involved in APAP metabolism, we reason that pattern of CYP1A2 expression will follow that of CYP2E1. To protect against the hepatotoxic affects of APAP, we hypothesize that CYP1A2 expression is down regulated during adaptive tolerance, mimicking the expression of CYP2E1. To test this hypothesis, we used real time RT-PCR and western blot analysis to compare the expression of CYP1A2 in an animal model that received a lethal dose of APAP to an animal model that received a lethal dose without the benefit of adaptive tolerance. Further, we compared the regulatory regions of the genetic sequence of CYP1A2 and CYP2E1. Software programs, Multalin version 5.4.1 and DiAlign version 3.1.2, were used to align and compare the two sequences.

This document is currently not available here.

Share

COinS
 

Down Regulation of CYP1A2 Expression Following Acetaminophen Exposure: Potential Implications on Adaptive Tolerance

As of 2003, acetaminophen (APAP)-induced hepatotoxicity became the leading cause of acute liver failure in the Unites States. When the major APAP metabolism route becomes saturated, hepatotoxicity results from a harmful metabolite called N-acetyl-p-benzoquinone imine (NAPQI). Cytochrome P450 1A2 (CYP1A2) and 2E1 (CYP2E1) are known to catalyze the production of NAPQI. The mechanisms leading to accidental overdose and death are not fully understood, however adaptive tolerance in mice has proven to protect them against a lethal dose. We hypothesize it is the down regulation of CYP2E1 during the period of toleration that accounts for the mice not succumbing to hepatotoxic affects of APAP. Because CYP1A2 is also involved in APAP metabolism, we reason that pattern of CYP1A2 expression will follow that of CYP2E1. To protect against the hepatotoxic affects of APAP, we hypothesize that CYP1A2 expression is down regulated during adaptive tolerance, mimicking the expression of CYP2E1. To test this hypothesis, we used real time RT-PCR and western blot analysis to compare the expression of CYP1A2 in an animal model that received a lethal dose of APAP to an animal model that received a lethal dose without the benefit of adaptive tolerance. Further, we compared the regulatory regions of the genetic sequence of CYP1A2 and CYP2E1. Software programs, Multalin version 5.4.1 and DiAlign version 3.1.2, were used to align and compare the two sequences.