Density functional study on the cytochrome-mediated S-oxidation: identification of crucial reactive intermediate on the metabolic path of thiazolidinediones.

S-Oxidation is an important cytochrome P450 (CYP450)-catalyzed reaction, and the structural and energetic details of this process can only be studied by using quantum chemical methods. Thiazolidinedione (TZD) ring metabolism involving initial S-oxidation leads to the generation of reactive metabolites (RMs) and subsequent toxicity forcing the withdrawal of the glitazone class of drugs, thus, the study of the biochemical pathway of TZD ring metabolism is a subject of interest. The S-oxidation of the TZD ring and the formation of the isocyanate intermediate (ISC) was implicated as a possible pathway; however, there are several questions still unanswered in this biochemical pathway. The current study focuses on the CYP450-mediated S-oxidation, fate of the sulfoxide product (TZDSO), ring cleavage to ISC, and formation of nucleophilic adducts. The process of S-oxidation was explored by using Cpd I (iron(IV)-oxo porphyrin, to mimic CYP450) at TZVP/6-311+G(d) basis set. The barriers were calculated after incorporating dispersion and solvent corrections. The metabolic conversion from TZDSO to ISC (studied at B3LYP/6-311++G(2df,3pd)//B3LYP/6-31+G(d)) required a novel protonated intermediate, TZDSOH(+). The effect of higher basis sets (6-311+G(d,p), aug-cc-pvqz) on this conversion was studied. TZDSOH(+) was observed to be more reactive and thermodynamically accessible than ISC, indicating that TZDSOH(+) is the actual reactive intermediate leading to toxicity of the TZD class of compounds.

Citation

Nikhil Taxak, Vaibhav A Dixit, Prasad V Bharatam. Density functional study on the cytochrome-mediated S-oxidation: identification of crucial reactive intermediate on the metabolic path of thiazolidinediones. The journal of physical chemistry. A. 2012 Oct 25;116(42):10441-50

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PMID: 23025570

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