Requirement for metabolic activation of acetylaminofluorene to induce multidrug gene expression.
Previously we have demonstrated that several xenobiotics can induce multidrug (mdr) gene expression in cultures of primary isolated hepatocytes. One of the best of these xenobiotic inducers in rat hepatocytes is 2-acetylaminofluorene (2-AAF), which induces mdr expression by an enhancement of mdr gene transcription. In all species studied to date, AAF is extensively and variously metabolized. In this study we have sought to determine if AAF per se or a metabolite is responsible for mediating the increase in mdr gene transcription and expression. This study demonstrates that AAF per se is not active, but that the effect of AAF we have observed on mdr gene transcription and expression in the rat is due to the formation of a reactive metabolite(s). Our data indicate that this reactive metabolite is probably N-acetoxy-2-aminofluorene or the sulfate ester of N-hydroxy-AAF. The requirement for the formation of one of these metabolites may explain the differences in species response to AAF, in terms of mdr gene expression, that we have observed. We hypothesize that the mechanism by which mdr gene transcription is increased in response to AAF involves a covalent interaction between a reactive metabolite and an mdr gene regulatory protein. Our current work is concerned with the exploration of this hypothesis.
Gant
T W
TW
National Cancer Institute, Bethesda, Maryland 20892.
Schrenk
D
D
Silverman
J A
JA
Thorgeirsson
S S
SS
D015073:2-Acetylaminofluorene / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D015073:2-Acetylaminofluorene