Precursors for cytochrome P450 profiling breath tests from an in silico screening approach

Abstract

The family of cytochrome P450 enzymes (CYPs) is a major player in the metabolism of drugs and xenobiotics. Genetic polymorphisms and transcriptional regulation give a complex patientindividual CYP activity profile for each human being. Therefore, personalized medicine demands easy and non-invasive measurement of the CYP phenotype. Breath tests detect volatile organic compounds (VOCs) in the patients' exhaled air after administration of a precursor molecule. CYP breath tests established for individual CYP isoforms are based on the detection of 13 CO 2 or 14 CO 2 originating from CYP-catalyzed oxidative degradation reactions of isotopically labeled precursors.We present an in silico work-flow aiming at the identification of novel precursor molecules, likely to result in VOCs other than CO 2 upon oxidative degradation as we aim at label-free precursor molecules. The ligand-based work-flow comprises five parts: (1) CYP profiling was encoded as a decision tree based on 2D molecular descriptors derived from established models in the literature and validated against publicly available data extracted from the DrugBank. (2) Likely sites of metabolism were identified by reactivity and accessibility estimation for abstractable hydrogen radical. (3) Oxidative degradation reactions (O-and N-dealkylations) were found to be most promising in the release of VOCs. Thus, the CYP-catalyzed oxidative degradation reaction was encoded as SMIRKS (a programming language style to implement reactions based on the SMARTS description) to enumerate possible reaction products. (4) A quantitative structure property relation (QSPR) model aiming to predict the Henry constant H was derived from data for 488 organic compounds and identifies potentially VOCs amongst CYP reaction products.(5) A blacklist of naturally occurring breath components was implemented to identify marker molecules allowing straightforward detection within the exhaled air.

The smell of longevity: a combination of Volatile Organic Compounds (VOCs) can discriminate centenarians and their offspring from age-matched subjects and young controls

“…The (patho)physiological conditions of the individuals create specific spectra of VOCs, detectable in sweat, exhaled breath, blood, urine, and feces (Amann et al 2014;Filipiak et al 2016), and an increasing number of studies indicate that specific VOCs profiles are disease-associated and can thus represent a possible tool to identify patients and/or monitor disease progression as they are strongly dependent on metabolism, inflammation, and infections. In particular, the alteration of specific biochemical mechanisms related to oxidative stress, cytochrome p450, carbohydrate, and lipid metabolism yields a VOCs profile that mirrors diseases of kidney, liver, and gastrointestinal tract, as well as neurodegenerative diseases and cancers (Lee et al 2009;Broza et al 2014;von Grafenstein et al 2014).…”