caa a22 4500 605487324 CHVBK 20210128100450.0 cr unu---uuuuu 210128e20150901xx s 000 0 eng 10.1007/s00214-015-1690-y doi (NATIONALLICENCE)springer-10.1007/s00214-015-1690-y Metabolic mechanisms of caffeine catalyzed by cytochrome P450 isoenzyme 1A2: a theoretical study [Elektronische Daten] [Zeqin Chen, Yuan Kang, Chenghua Zhang, Jing Tao, Ying Xue] Caffeine (CA), a universally used psychoactive substance in foods and drugs, can cause osteoporosis when taken in moderate-to-high doses. The metabolic mechanisms of CA catalyzed by cytochrome P450 isoenzyme 1A2 (CYP1A2) were systematically explored in this study based on DFT calculation. Four possible metabolic pathways were investigated, namely 1-N, 3-N, 7-N demethylations, and C-8 hydroxylation. The results determined the mechanistic details and revealed some notable features. The rate-limiting C α -H hydroxylation for the N-demethylation mechanism proceeded predominantly through a hydrogen atom transfer mechanism with two-state reactivity. The generated carbinolamine decomposed in a non-enzymatic environment, especially through the adjacent heteroatom-assisted proton transfer. The rate-limiting step for C-8 hydroxylation involved the nucleophilic attack of the active Cpd I's oxygen atom. Intriguingly, CA metabolic performance depended on the multiplicity of Cpd I. The 3-N demethylation metabolic mechanism predominated over the C-8 hydroxylation on the high-spin quartet state. Paraxanthine was the most energetically feasible metabolic product of CA. On the low-spin doublet state, however, C-8 hydroxylation had the lowest activation energy; hence, 1,3,7-trimethyluric acid was the optimum metabolic product of CA. All the results were in agreement with the experimental observation and can supply rational clues for the different metabolic performances of CA catalyzed by CYP1A2 in humans and rats. The calculated results in this study can provide more implications for the controversial amine N-dealkylation mechanisms by CYP and offer essential insights into bio-decaffeination techniques. Springer-Verlag Berlin Heidelberg, 2015 Caffeine nationallicence CYP1A2 nationallicence N-demethylation nationallicence Hydroxylation nationallicence Density functional theoretical calculation nationallicence Kinetic isotope effect nationallicence Chen Zeqin College of Chemistry and Chemical Engineering, Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, China West Normal University, 637002, Nanchong, People's Republic of China aut Kang Yuan College of Chemistry and Chemical Engineering, Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, China West Normal University, 637002, Nanchong, People's Republic of China aut Zhang Chenghua School of Basic Medical Sciences, North Sichuan Medical College, 637007, Nanchong, People's Republic of China aut Tao Jing College of Chemistry and Chemical Engineering, Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, China West Normal University, 637002, Nanchong, People's Republic of China aut Xue Ying College of Chemistry, Key Laboratory of Green Chemistry and Technology in Ministry of Education, Sichuan University, 610064, Chengdu, People's Republic of China aut Theoretical Chemistry Accounts Springer Berlin Heidelberg 134/9(2015-09-01), 1-14 1432-881X 134:9<1 2015 134 214 https://doi.org/10.1007/s00214-015-1690-y text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00214-015-1690-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Chen Zeqin College of Chemistry and Chemical Engineering, Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, China West Normal University, 637002, Nanchong, People's Republic of China aut NATIONALLICENCE 700 1- Kang Yuan College of Chemistry and Chemical Engineering, Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, China West Normal University, 637002, Nanchong, People's Republic of China aut NATIONALLICENCE 700 1- Zhang Chenghua School of Basic Medical Sciences, North Sichuan Medical College, 637007, Nanchong, People's Republic of China aut NATIONALLICENCE 700 1- Tao Jing College of Chemistry and Chemical Engineering, Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, China West Normal University, 637002, Nanchong, People's Republic of China aut NATIONALLICENCE 700 1- Xue Ying College of Chemistry, Key Laboratory of Green Chemistry and Technology in Ministry of Education, Sichuan University, 610064, Chengdu, People's Republic of China aut NATIONALLICENCE 773 0- Theoretical Chemistry Accounts Springer Berlin Heidelberg 134/9(2015-09-01), 1-14 1432-881X 134:9<1 2015 134 214