Formation/Fate of Reactive Metabolites from General Anesthetics and A Comparison of Toxic and Non-Toxic Analogues: A DFT Study
Vaibhav A. Dixit,
Prasad V. Bharatam.
Chloroform and Halothane are well known hepatotoxic anesthetics for which toxicity is attributed to their
reactive metabolites. The molecular level details of reactions leading to the formation of reactive metabolites from
chloroform and halothane have not been explored. Potential energy surface (PES) for the formation of phosgene (a toxic
intermediate) from Chloroform has been studied using quantum chemical methods. The HOOH mediated reaction of
chloroform to give phosgene has been found to be exothermic by 81.24 kcal/mol with a barrier of ~ 3 kcal/mol through
the water catalyzed transition sate. The quantum chemical studies on the reactivity profile of phosgene indicated that urea
derivatives need to be considered on the mechanism leading to toxicity. Similarly, metabolic pathways of Halothane
oxidation have been studied. The C-H bond dissociation energies (BDE) and radical stabilization energies (RSE) for
Chloroform and Halothane (< 95 kcal/mol and > 10 kcal/mol) were found to be significantly different for these toxic
anesthetics in comparison to their safer analogues (> 100 kcal/mol and < 5 kcal/mol) respectively; thus these parameters
can be employed to distinguish toxic and non-toxic general anesthetics. Enthalpy for the Cpd I, a widely used model for
CYP450 enzymes, mediated reactions also agreed well with these results.
Keywords: General anesthetics, DFT study, toxicity, metabolism, haloalkanes, Radical Stabilization Energy.
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