RT Journal Article
SR Electronic
T1 Roles of Human CYP2A6 and Monkey CYP2A24 and 2A26 Cytochrome P450 Enzymes in the Oxidation of 2,5,2′,5′-Tetrachlorobiphenyl
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1899
OP 1909
DO 10.1124/dmd.116.072991
VO 44
IS 12
A1 Tsutomu Shimada
A1 Kensaku Kakimoto
A1 Shigeo Takenaka
A1 Nobuyuki Koga
A1 Shotaro Uehara
A1 Norie Murayama
A1 Hiroshi Yamazaki
A1 Donghak Kim
A1 F. Peter Guengerich
A1 Masayuki Komori
YR 2016
UL http://dmd.aspetjournals.org/content/44/12/1899.abstract
AB 2,5,2′,5′-Tetrachlorobiphenyl (TCB) induced type I binding spectra with cytochrome P450 (P450) 2A6 and 2A13, with Ks values of 9.4 and 0.51 µM, respectively. However, CYP2A6 oxidized 2,5,2′,5′-TCB to form 4-hydroxylated products at a much higher rate (∼1.0 minute−1) than CYP2A13 (∼0.02 minute−1) based on analysis by liquid chromatography–tandem mass spectrometry. Formation of 4-hydroxy-2,5,2′,5′-TCB by CYP2A6 was greater than that of 3-hydroxy-2,5,2′,5′-TCB and three other hydroxylated products. Several human P450 enzymes, including CYP1A1, 1A2, 1B1, 2B6, 2D6, 2E1, 2C9, and 3A4, did not show any detectable activities in oxidizing 2,5,2′,5′-TCB. Cynomolgus monkey CYP2A24, which shows 95% amino acid identity to human CYP2A6, catalyzed 4-hydroxylation of 2,5,2′,5′-TCB at a higher rate (∼0.3 minute−1) than CYP2A26 (93% identity to CYP2A6, ∼0.13 minute−1) and CYP2A23 (94% identity to CYP2A13, ∼0.008 minute−1). None of these human and monkey CYP2A enzymes were catalytically active in oxidizing other TCB congeners, such as 2,4,3′,4′-, 3,4,3′,4′-, and 3,5,3′,5′-TCB. Molecular docking analysis suggested that there are different orientations of interaction of 2,5,2′,5′-TCB with the active sites (over the heme) of human and monkey CYP2A enzymes, and that ligand interaction energies (U values) of bound protein-ligand complexes show structural relationships of interaction of TCBs and other ligands with active sites of CYP2A enzymes. Catalytic differences in human and monkey CYP2A enzymes in the oxidation of 2,5,2′,5′-TCB are suggested to be due to amino acid changes at substrate recognition sites, i.e., V110L, I209S, I300F, V365M, S369G, and R372H, based on the comparison of primary sequences.