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Theoretical elucidation of the metabolic mechanisms of phenothiazine neuroleptic chlorpromazine catalyzed by cytochrome P450 isoenzyme 1A2

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Abstract

Chlorpromazine, belonging to the first-generation antipsychotics, is known to cause some side effects, such as hepatotoxicity and agranulocytosis. The metabolic mechanisms of chlorpromazine remain elusive up to now, but are thought to result in the formation of some reactive metabolites having side effects on the parent drug. The goal of this work was to explore the metabolic mechanisms of chlorpromazine catalyzed by cytochrome P450 isoenzyme 1A2, a highly important activating enzyme of cytochrome P450 family, using DFT calculation. Three types of metabolic mechanisms were characterized, including S-oxidation, aromatic hydroxylation and N-dealkylation. The calculated results demonstrate that N 14-demethylation is the most thermodynamically and kinetically favorable metabolic pathway of chlorpromazine, followed by S5-oxidation. Then, mono-N-desmethylchlorpromazine is the most feasible chlorpromazine metabolite, which can occur further demethylation to form di-N-desmethylchlorpromazine. Besides, chlorpromazine 5-sulfoxide and 7-hydroxychlorpromazine are both the possible metabolites of chlorpromazine. Interestingly, N-methyl hydroxylation, the rate-limiting step of N-demethylation, proceeds predominantly via a single-electron-transfer mechanism. All the proton transfer processes involved in the aromatic hydroxylation and N-dealkylation prefer to occurrence in a water-assisted enzymatic process. Each metabolic pathway proceeds in the spin-selective manner via the low-spin state of Cpd I. Our results are in good accordance with the experimental observations, which can provide some essential implications for the metabolic mechanisms of chlorpromazine-like drugs.

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Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (Grant No. 21203153), Science and Technology Department of Sichuan Province (Grant No. 2011JY0136) and Department of Education of Sichuan Province (Grant No. 12ZA174) and China West Normal University (Grant No. 11B002).

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    Authors and Affiliations

    1. College of Chemistry and Chemical Engineering, Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, China West Normal University, Nanchong, 637002, People’s Republic of China

      Zhiyu Xue, Yan Zhang, **g Tao, Yuan Kang & Zeqin Chen

    2. College of Chemistry, Key Laboratory of Green Chemistry and Technology in Ministry of Education, Sichuan University, Chengdu, 610064, People’s Republic of China

      Zhiyu Xue, Yan Zhang & Ying Xue

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    1. Zhiyu Xue
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    2. Yan Zhang
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    3. **g Tao
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    4. Yuan Kang
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    Correspondence to Zeqin Chen.

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    Zhiyu Xue and Yan Zhang authors have contributed equally to this work.

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    Xue, Z., Zhang, Y., Tao, J. et al. Theoretical elucidation of the metabolic mechanisms of phenothiazine neuroleptic chlorpromazine catalyzed by cytochrome P450 isoenzyme 1A2. Theor Chem Acc 135, 218 (2016). https://doi.org/10.1007/s00214-016-1943-4

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