Mathematically modelling the induction of xenobiotic-metabolising and transporter enzymes
Mohammed Atari, Paul Metcalfe, and Simon Thomas, Cyprotex Discovery Limited, UK
Living organisms are generally exposed to numerous foreign and endogenous substances, including both drugs and environmental chemicals, that can have a profound influence on their health. Toxic effects are important for both environmental chemicals and in the pharmaceutical industry, where toxicity is a leading cause of late-stage attrition (the termination of a drug candidate in the development phase). Developing new chemicals is becoming more costly and more difficult, therefore, the traditional approach for toxicological testing is moving towards in silico predictive toxicology techniques that provide a fast and cost effective alternative (or supplement) to bioassays to identify toxic effects at early stages of product development and can be applied without a physically available compound.
Xenobiotic-metabolising enzymes and transporter proteins play crucial roles in the metabolism and disposition of compounds: metabolism can result in toxification and/or detoxification, and transport can either remove chemicals from the body or cause increased chemical concentrations in certain tissues and hence increase toxic effects. Some compounds affect their own metabolism and disposition by altering the transcription of the genes coding for the metabolism and transporter proteins. This is modulated by the nuclear receptor superfamily; a compound binds to a nuclear receptor and hence affects gene transcription. In addition, the expression and activity of these proteins varies between individuals which is determined by factors including but not limited to sexual variability.
To investigate the effect of typical nuclear receptor activators on the induction of the enzymes that govern xenobiotic metabolism and disposition in human hepatocytes, a novel mathematical model for the in vitro kinetics of chemicals has been developed. This model describes the expression of cytochrome P450 enzymes and ATP-binding cassette transporters in response to different activators. Moreover, the model accounts for sexual dimorphism, which affects both the concerted activities of interconnected genes regulated by NRs and the level of individual gene expression. Such a model, once fully validated, has the potential for enhancing the design of optimal dosing regimens in the preclinical assessment of toxic effects and in improving the interpretation of in vitro experiments.
