Modulation of Phase II Drug Metabolizing Enzyme Activities by N-Heterocycles

Drugs and other chemicals that contain one or more heterocyclic nitrogen atoms are most widely known for their ability to both inhibit and induce cytochrome P450s. Their ability to affect a wide range of Phase II drug metabolizing enzyme activities has received much less attention and exposure. For some N-heterocycles, induction of Phase II metabolism occurs in the absence of induction effects on cytochrome P450, a property with potential utility in reducing drug and chemical toxicity (chemoprotection). The mechanism of this induction, and an accounting of the Phase II selectivity, has not been rigorously investigated. This review gathers and documents existing information on the simultaneous inductive effects of N-heterocycles on glucuronidation, sulfation (sulfonation) and glutathione conjugation reactions, as well epoxide hydrolase and quinone oxidoreductase activities. Basic information on cytochrome P450 induction is provided for comparative purposes. The review will serve as a base for any future interest in the phenomenon. The existing information on enzyme changes derives largely from laboratory animal studies. Chemicals investigated range from both simple and complex pyridines and imidazoles to benzoquinolines and phenanthrolines. Isomeric differences can have a major impact on induction characteristics and Phase II selectivity. Promising indications for the effectiveness of N-heterocycle elicited enzyme changes in chemoprotection in vivo awaits investigation.