Modeling of interactions between xenobiotics and cytochrome P450 (CYP) enzymes

Abstract

The adverse effects to humans and environment of only few chemicals are well known. Absorption, distribution, metabolism, and excretion (ADME) are the steps of pharmaco/toxicokinetics that determine the internal dose of chemicals to which the organism is exposed. Of all the xenobiotic-metabolizing enzymes, the cytochrome P450 (CYP) enzymes are the most important due to their abundance and versatility. Reactions catalyzed by CYPs usually turn xenobiotics to harmless and excretable metabolites, but sometimes an innocuous xenobiotic is transformed into a toxic metabolite. Data on ADME and toxicity properties of compounds are increasingly generated using in vitro and modeling (in silico) tools. Both physics-based and empirical modeling approaches are used. Numerous ligand-based and target-based as well as combined modeling methods have been employed to evaluate determinants of CYP ligand binding as well as predicting sites of metabolism and inhibition characteristics of test molecules. In silico prediction of CYP–ligand interactions have made crucial contributions in understanding (1) determinants of CYP ligand binding recognition and affinity; (2) prediction of likely metabolites from substrates; (3) prediction of inhibitors and their inhibition potency. Truly predictive models of toxic outcomes cannot be created without incorporating metabolic characteristics; in silico methods help producing such information and filling gaps in experimentally derived data. Currently modeling methods are not mature enough to replace standard in vitro and in vivo approaches, but they are already used as an important component in risk assessment of drugs and other chemicals.

Planarian brain regeneration as a model system for developmental neurotoxicology

“…In humans, a large portion of xenobiotic metabolism is performed by cytochrome P450s (Raunio et al. ). Analysis of the S. mediterranea genome (Robb et al.…”

Computational chemical biology and drug design: Facilitating protein structure, function, and modulation studies

“…In addition to these comprehensive platforms, many free tools have been developed to predict a certain aspect of ADMET, mainly with a focus on metabolism and toxicity. Several articles have summarized the currently available software for predicting CYP450‐mediated metabolism . In addition, Lazar (http://lazar.in-silico.ch/predict) can predict various toxicity indices, including acute toxicity, mutagenicity, and carcinogenicity .…”

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Controlling the Regioselectivity of Fatty Acid Hydroxylation (C10) at α‐ and β‐Position by CYP152A1 (P450Bsβ) Variants

“…Cytochrome P450 enzymes (CYPs) are heme proteins, which are found in many living organisms. CYPs are important detoxification enzymes, as they turn apolar compounds more polar via hydroxylation, which allows subsequent excretion . Besides the C−H oxidation, P450s catalyze a vast variety of reactions such as decarboxylation, dehalogenation, epoxidation, amine/oxygen dealkylation, sulfoxidation, anti‐Markovnikov oxidation and in case of cytochrome c C−Si and C−B bond formation …”