Theoretical study on the metabolic mechanisms of levmepromazine by cytochrome P450.
Levomepromazine, an "older" typical neuroleptic, is widely applied in psychiatry for the treatment of schizophrenia. The biotransformation of Levomepromazine remains elusive up to now, but found to result in the formation of different derivatives that may contribute to the therapeutic and/or side-effects of the parent drug. The present work aims to resolve the metabolic details of Levomepromazine catalyzed by cytochrome P450, an important heme-containing enzyme superfamily, based on DFT calculation. Two main metabolic pathways have been addressed, S-oxidation and N-demethylation. The mechanistic conclusions have revealed a stepwise transfer of two electrons mechanism in S-oxidation reaction. N-demethylation is a two-step reaction, including the rate-determining N-methyl hydroxylation which proceeds via the single electron transfer (SET) mechanism and the subsequent C-N bond fission through a water-assisted enzymatic proton-transfer process. N-demethylation is more feasible than S-oxidation due to its lower activation energy and N-desmethyllevomepromazine therefore is the most plausible metabolite of Levomepromazine. Each metabolic pathway proceeds in a spin-selective manner (SSM) mechanism, predominately via the LS state of Cpd I. Our observations are in good accordance with the experimental results, which can provide some general implications for the metabolic mechanism of Levomepromazine-like drugs. Graphical abstract The metabolic mechanisms of levmepromazine by cytochrome P450.
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.
Yongting
Y
Wang
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.
Qiu
Q
Chen
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
Z
Xue
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.
Yan
Y
Zhang
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. chenzeqin@cwnu.edu.cn.
Zeqin
Z
Chen
College of Chemistry, Key Laboratory of Green Chemistry and Technology in Ministry of Education, Sichuan University, Chengdu, 610064, People's Republic of China.
Ying
Y
Xue
D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004583:Electrons; D006801:Humans; D006900:Hydroxylation; D053858:Metabolic Networks and Pathways / Q000502:physiology; D008728:Methotrimeprazine / Q000031:analogs & derivatives / Q000378:metabolism*; D010084:Oxidation-Reduction; D011522:Protons
D011522:Protons; C044467:N-desmethyllevomepromazine; D003577:Cytochrome P-450 Enzyme System; D008728:Methotrimeprazine
Cytochrome P450; Levomepromazine; Metabolic mechanism; N-demethylation; S-oxidation