Establishment of the experimental procedure for prediction of conjugation capacity in mutant UGT1A1

Autoři: Yutaka Takaoka aff001;  Atsuko Takeuchi aff002;  Aki Sugano aff001;  Kenji Miura aff001;  Mika Ohta aff001;  Takashi Suzuki aff001;  Daisuke Kobayashi aff003;  Takuji Kimura aff004;  Juichi Sato aff004;  Nobutaro Ban aff004;  Hisahide Nishio aff006;  Toshiyuki Sakaeda aff007
Působiště autorů: Division of Medical Informatics and Bioinformatics, Kobe University Hospital, Kobe, Japan aff001;  Division of Analytical Laboratory, Kobe Pharmaceutical University, Kobe, Japan aff002;  Division of Medical and Healthcare Systems, Healthcare Economics and Hospital Administration, Kobe University Graduate School of Medicine, Kobe, Japan aff003;  Department of General Medicine/Family and Community Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan aff004;  Medical Education Center, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan aff005;  Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan aff006;  Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan aff007
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225244


UDP-glucuronosyltransferase 1A1 (UGT1A1) is an enzyme that is found in the endoplasmic reticulum membrane and can reportedly have a large number of amino acid substitutions that result in the reduction of glucuronidation capacity. For example, adverse drug reactions when patients receive CPT-11 (irinotecan) such as in cancer chemotherapy are caused by amino acid substitutions in UGT1A1. We previously found that the extent of the docking when the hydroxyl residue of bilirubin was oriented toward UDP-glucuronic acid correlated with in vitro conjugation capacity. In this study, we analyzed the conformation of mutant UGT1A1s by means of structural optimization with water and lipid bilayers instead of the optimization in vacuo that we used in our previous study. We then derived a mathematical model that can predict the conjugation capacities of mutant UGT1A1s by using results of substrate docking in silico and results of in vitro analysis of glucuronidation of acetaminophen and 17β-estradiol by UGT1A1s. This experimental procedure showed that the in silico conjugation capacities of other mutant UGT1A1s with bilirubin or SN-38 were similar to reported in vitro conjugation capacities. Our results suggest that this experimental procedure described herein can correctly predict the conjugation capacities of mutant UGT1A1s and any substrate.

Klíčová slova:

Amino acid analysis – bilirubin – Drug metabolism – Enzyme metabolism – Mathematical models – Simulation and modeling – Substitution mutation – Coenzymes


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