Density Functional Study on the Cytochrome-Mediated S-Oxidation: Identification of Crucial Reactive Intermediate on the Metabolic Path of Thiazolidinediones

Abstract

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.

Cytotoxicity of thiazolidinedione-, oxazolidinedione- and pyrrolidinedione-ring containing compounds in HepG2 cells

“…The TZD ring may be an important structural feature in hepatotoxicity of the glitazones (Alvarez-Sanchez et al, 2006; He et al, 2004; Kassahun et al, 2001; Taxak et al, 2012; Tettey et al, 2001) and DCPT (Kennedy et al, 2003; Patel et al, 2012). In addition, structural modifications to DCPT, where the TZD ring had a 5-methyl substituent or was replaced with isomeric 2- or 4-thiazolidinone rings, reduced or eliminated cytotoxicity to HepG2 cells (Frederick et al, 2011).…”

“…Furthermore, there is conflicting evidence in the literature as to whether TGZ itself or a metabolite causes liver damage (Masubuchi, 2006). Glutathione (GSH) trapping experiments and quantum chemical modeling studies have provided evidence that reactive intermediates can be generated from an initial cytochrome P450 (CYP)-mediated sulfoxidation in the thiazolidinedione (TZD) ring of TGZ (Alvarez-Sanchez et al, 2006; He et al, 2004; Kassahun et al, 2001; Taxak et al, 2012; Tettey et al, 2001). …”

Advances in Computational Prediction of Regioselective and Isoform-Specific Drug Metabolism Catalyzed by CYP450s.

“…Taxak et al. have explained how water catalyzed rearrangement of thiazolidinedione S‐oxide, formed by CYP450 mediated oxidation of thiazolidinedione ring, leads to formation of toxic isocyanate RM (Figure 8) . This information has recently been used by Bordessa et al.…”

“…Three out of four MD simulations were found suitable to further analysis of the proposed metabolic pathways. As seen by many other investigators oxidation on the doublet potential energy surface is more favorable than on the quartet potential energy surface . Boltzmann‐weighted averaging method was employed to calculate the overall barriers to the reaction.…”

“…In addition if, metabolism leads to the formation of reactive metabolite (RM), rearrangement of the structure may ensue to give an unexpected product metabolite e.g. S‐oxidation followed by rearrangement to isocyanate metabolites in thiazolidinediones and oxidation of haloalkanes followed by loss of hydrogen halides . Thus the subtle difference in how the SOM is defined by the computational and experimental scientists needs to be resolved.…”