DRUG INDUCTION OF P450 GENES: HISTORY, MECHANISM, AND IMPLICATION

Abstract

Cells are endowed with mechanisms to protect them from chemical insults. One of such mechanisms is metabolism of chemicals that can be either endogenous, naturally-occurring, or synthetic origin. The metabolisms primarily occur in liver that is followed by kidney and intestine. In general, chemicals are first metabolized by P450 (CYP) enzymes and subsequently are conjugated by transferases, called the Phase I and Phase II enzymes, respectively. To maximize metabolic capability, liver cells induce metabolizing enzymes and also drug transporters. Although induction can be regulated at various steps during synthesis of enzyme proteins, gene transcription plays the primary role in the regulation. There are three major mechanisms that mediate drug-inducible gene transcription: Ah receptor (AhR)-mediated, Nrf2-mediated, and nuclear receptor-mediated mechanisms.