Deciphering Key Interactions of Ligands with CYP3A4-Template* system

Yasushi Yamazoe; Takashi Yamada; Akihiko Hirose; Norie Murayama

doi:10.14252/foodsafetyfscj.D-20-00023

Deciphering Key Interactions of Ligands with CYP3A4-Template* system

Food Saf (Tokyo). 2021 Feb 10;9(1):10-21. doi: 10.14252/foodsafetyfscj.D-20-00023. eCollection 2021 Mar.

Authors

Yasushi Yamazoe^{1

2}, Takashi Yamada², Akihiko Hirose², Norie Murayama³

Affiliations

¹ Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan.
² Division of Risk Assessment, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki-ku, Kawasaki 210-9501, Japan.
³ Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo194-8543, Japan.

Abstract

Cytochrome P450 (CYP)-mediated metabolisms are often associated with biological and toxicological events of chemicals. A major hepatic enzyme, CYP3A4, showed clear distinctions on their catalyses even among ligands having resemble structures. To better understand mechanisms of their distinct catalyses, possible associations of ligand interactions at specific parts of CYP3A4 residues were investigated using CYP3A4-Template system developed (DMPK 2019 and 2020). A placement was available selectively for CYP3A4-mediated R-thalidomide 5-oxidation on Template, but not for the 5'-oxidation and the S-isomer oxidations. Similar placements were generated for pomalidomide (4-amino-thalidomide), but not for a poor ligand, lenalidomide (3-deoxy-pomalidomide). The latter ligand took placements lacking IJK-Interaction or sticking the 4-amino part beyond the facial-side wall on Template. A placement was available for the tert-butyl oxidation of terfenadine, but not for an analog, ebastine. Their interactions with upper-Cavity-2 residue were expected to differ at their sites of oxygen substituents. Some phenolic antioxidants behave distinctly toward biological oxidations in vitro and in vivo. Butylated hydroxytoluene is oxidized to the peroxy-derivative in vitro, but solely to the oxidized metabolites at the benzyl and tert-butyl methyl positions in vivo. Involvement of CYP3A4 were suggested for all the three reactions from the placements on Template. Tocopherols were also applied on Template for the oxidations for chroman and side-chain terminals. The primary placement was suggested to undergo the futile-recycling through formation of the peroxide intermediate subsequently to lead the substantial lack of the CYP3A4-mediated oxidation. These data suggest the effectiveness of CYP3A4-Template assessment to understand the causal basis of poor oxidations and also to verify the in vivo contribution of CYP3A4-mediated peroxidative reactions.

Keywords: BHT; Keywordsthalidomide; acetaminophen; ebastine; lenalidomide; tocopherols.