Inhibition and induction of human cytochrome P450 enzymes: current status

Abstract

Variability of drug metabolism, especially that of the most important phase I enzymes or cytochrome P450 (CYP) enzymes, is an important complicating factor in many areas of pharmacology and toxicology, in drug development, preclinical toxicity studies, clinical trials, drug therapy, environmental exposures and risk assessment. These frequently enormous consequences in mind, predictive and pre-emptying measures have been a top priority in both pharmacology and toxicology. This means the development of predictive in vitro approaches. The sound prediction is always based on the firm background of basic research on the phenomena of inhibition and induction and their underlying mechanisms; consequently the description of these aspects is the purpose of this review. We cover both inhibition and induction of CYP enzymes, always keeping in mind the basic mechanisms on which to build predictive and preventive in vitro approaches. Just because validation is an essential part of any in vitro-in vivo extrapolation scenario, we cover also necessary in vivo research and findings in order to provide a proper view to justify in vitro approaches and observations.

Enzymatic activity in turkey, duck, quail and chicken liver microsomes against four human cytochrome P450 prototype substrates and aflatoxin B1

“…3 One of the most important advantages of using selective enzyme substrates is to be able to determine the role of an enzyme in a specific biochemical reaction. 4,5 The use of this kind of molecules with differential specificities and the effect of these molecules on directed enzymatic reactions has been a useful tool to identify enzymes related with the biotransformation of certain xenobiotics, endogenous metabolites and drugs. [6][7][8][9] A widely used strategy to identify an enzyme involved in a metabolic pathway is to correlate the prototype enzymatic activity with the target substrate molecule activity.…”

Human monocyte-derived cells with individual hepatocyte characteristics: a novel tool for personalized in vitro studies

“…The CYPs 1A2, 2A6, 2B6, 2D6, 2E1, 3A4 and 3A5 are found in hepatocytes with great abundance. 1 Most CYP enzymes can be induced, that is, their activity in the hepatocyte is increased to manage greater amounts of xenobiotics. This induction is mediated by receptors, such as the pregnane-X-receptor (PXR), 2 the aryl-hydrocarbon receptor 3 and the constitutive androestendione receptor.…”

“…This induction is mediated by receptors, such as the pregnane-X-receptor (PXR), 2 the aryl-hydrocarbon receptor 3 and the constitutive androestendione receptor. 1 Knowing the way a substance is metabolized and how a substance interacts with co-medication is crucial for modern drug design. Therefore, hepatocyte models are urgently needed for drug development, because no other cell possesses a comparable equipment of metabolism pathways.…”

Low-dose extrapolation in toxicology: an old controversy revisited

“…Extrapolation to in vivo relevant concentrations (Sogorb et al 2007;Glahn et al 2008;Schug et al 2008;Borza et al 2008), dose-response relationships (Dorn et al 2008;O'Brien et al 2006;Pelkonen et al 2008, Levy et al 2007, and toxicity testing strategies (Lilienblum et al 2008;Greim 2007;Blaauboer and Andersen 2007;Naraharisetti et al 2008;Kanno et al 2008;Hewitt et al 2007;Chan et al 2008) are among the cutting-edge topics reported in our journal. Therefore, the authors are happy that Edward J. Calabrese from the University of Massachusetts has contributed two review articles to this edition of the Archives of Toxicology:…”