title: An epoxidation mechanism of carbamazepine by CYP3A4.
abstract: Human CYP3A4 catalyzes the 10,11-epoxidation of carbamazepine (CBZ). However, the epoxide is less stable in terms of potential energy than hydroxides of the six-membered aromatic ring. To clarify the reason why CYP3A4 produces such an energetically unfavorable compound, the mechanism of epoxidation of CBZ by CYP3A4 was investigated by theoretical calculations. The reaction consisted of two elementary processes in which two C-O bonds were generated stepwise. The rate-determining step was the first one and the activation energy was 21.3kcal/mol at the DFT (B3LYP/6-31G( * *)) level. The activation energy level of the first step of the 10,11-epoxidation was lower than that of the hydroxylation of the aromatic ring. For this reason, 10,11-epoxidation is more probable than hydroxylation of the aromatic ring, and only 10,11-epoxide is formed.
authors: Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan. mhata@cc.matsuyama-u.ac.jp
authors: Masayuki
authors: M
authors: Hata
authors: Yoshikazu
authors: Y
authors: Tanaka
authors: Naoko
authors: N
authors: Kyoda
authors: Taisuke
authors: T
authors: Osakabe
authors: Hitomi
authors: H
authors: Yuki
authors: Itsuko
authors: I
authors: Ishii
authors: Mitsukazu
authors: M
authors: Kitada
authors: Saburo
authors: S
authors: Neya
authors: Tyuji
authors: T
authors: Hoshino
mesh_terms: D001665:Binding Sites; D002220:Carbamazepine / Q000737:chemistry*; D002384:Catalysis; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry*; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D006900:Hydroxylation; D008956:Models, Chemical; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011789:Quantum Theory; D013329:Structure-Activity Relationship
chemical_list: D004852:Epoxy Compounds; D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human