Cytochrome P450 Enzymes Mechanism Based Inhibitors: Common Sub-Structures and Reactivity

Abstract

The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms which can lead to drug-drug interactions. The inhibition of CYPs can be reversible (competitive or non-competitive) or irreversible. Irreversible inhibition usually derives from activation of a drug by CYPs into a reactive metabolite, which tightly binds to the enzyme active site, leading to a long lasting inactivation. This process is called "mechanism based inhibition" or "suicide inhibition". The irreversible inactivation usually implies the formation of a covalent bond between the metabolite and the enzyme, which can lead to hapten formation and can in some cases trigger an autoimmune-response. For these reasons it is of utmost importance to study the mechanism of the CYP inhibition of new potential drugs as early as possible during the drug discovery process. The literature on CYPs is vast and covers numerous aspects of their biology and biochemistry, however to our knowledge there is no general and systematic review focusing on mechanism-based inhibitors; we have reviewed the literature and compiled all the available data on chemical entities, which are known to be CYP suicide inhibitors. Each compound is reported together with its chemical structure, the CYP isoform and the parameters describing the inactivation. Literature references are reported together with their PMID (PubMed ID number) to allow a fast retrieval of the papers. This review offers a quick reference to help predict liabilities of new chemical entities without carrying out extensive in vitro work, and will hopefully help in designing safer drugs.

Selective, competitive and mechanism-based inhibitors of human cytochrome P450 2J2

“…At the opposite, the affinity of 5 for CYP2J2 seems to be higher than that of 13, as suggested by the K I (0.45 ± 0.05 and 2.9 ± 0.2 μM respectively, Table 4) and IC 50 values (0.4 ± 0.1 and 6.7 ± 2 μM, respectively, Table 1) found for these compounds. Table 4 also compares kinetic constants reported for other CYP mechanism-based inactivators [56]. It indicates that 5 and 13 are reasonably efficient mechanism-based inactivators of CYP2J2, as judged from their k inact /K I values.…”

“…Most of them derive from terfenadone by replacement of its t-butyl group with various R groups of different size and polarity. This includes R groups bearing chemical functions well known to lead to suicide inactivation of cytochrome P450 after in situ oxidation [52][53][54][55][56]. This is the case of the terminal double bond of compound 5, of the CHF 2 function of compound 12, and of the benzo-1,3-dioxole function of compound 13 ( Table 1).…”

The Conduct of Drug Metabolism Studies Considered Good Practice (II): In Vitro Experiments

“…The recently established CYP phenotyping reaction focuses on determining the CYP isoform involved in the metabolism of a given drug [12]; The list of phenotyped compounds continues to grow [13]. Before conducting CYP phenotyping, however, it is important first to define the predominant clearance mechanisms for the investigational drug in question.…”

“…This process is called "mechanism based inhibition" or "suicide inhibition". Fontana et al presented a general and systematic review with this regard [13].…”

Neuroimaging - Clinical Applications

“…A major concern with acetylenes in potential drugs is the possibility of chemical or metabolic reactivity (Milbank et al, 2007). Terminal acetylenes are well known to be mechanism-based CYP-inactivators (Testa & Jenner, 1981) and there is an increasing body of information suggesting that internal acetylenes can be activated by CYPs (Fontana et al, 2005;Foroozesh et al, 1997;Shimada et al, 2007) or even undergo uncatalyzed addition of glutathione Mutlib et al, 1999). Mutlib et al reported that incubation of MPEP with triple-labeled glutathione gave compounds with molecular weights and fragmentations consistent with both activated and unactivated addition of GSH to the alkyne (Mutlib et al, 2005).…”