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©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
Superior gallstone dissolubility and safety of tert-amyl ethyl ether over methyl-tertiary butyl ether
Dong Do You, Suk Joon Cho, Ok-Hee Kim, Jin Sook Song, Kyu-Seok Hwang, Sang Chul Lee, Kee-Hwan Kim, Ho Joong Choi, Ha-Eun Hong, Haeyeon Seo, Tae Ho Hong, Jung Hyun Park, Tae Yoon Lee, Joseph Ahn, Jae-Kyung Jung, Kwan-Young Jung, Say-June Kim
Dong Do You, Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul 16247, South Korea
Suk Joon Cho, Jae-Kyung Jung, College of Pharmacy, Chungbuk National University, Cheongju 28644, South Korea
Ok-Hee Kim, Ho Joong Choi, Tae Ho Hong, Tae Yoon Lee, Joseph Ahn, Say-June Kim, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
Ok-Hee Kim, Ha-Eun Hong, Haeyeon Seo, Say-June Kim, Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
Jin Sook Song, Kyu-Seok Hwang, Kwan-Young Jung, Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea
Sang Chul Lee, Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul 34943, South Korea
Kee-Hwan Kim, Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul 11765, South Korea
Ha-Eun Hong, Haeyeon Seo, Department of Biomedicine and Health Science, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
Jung Hyun Park, Department of Surgery, Eunpyeong St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 03312, South Korea
Kwan-Young Jung, Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon 34113, South Korea
Author contributions: Kim SJ was responsible for obtaining funds, planning the study, data interpretation and manuscript preparation; You DD and Kim SJ drafted the paper and participated in the animal experiments; Cho SJ and Jung KY developed contact litholytic agents (TAEE), and performed chemical experiments, such as thermogravimetric analysis; Song JS, Hwang KS, and Jung JK took responsibility of various in vitro and in vivo toxicity tests, including the measurement of zebrafish locomotor activity; Kim OH, Hong HE, and Seo HY principally involved in the in vitro experiments; Lee SC, Kim KH, Choi HJ, Hong TH, Park JH, Lee TY, and Ahn J were contributed to acquisition of human gallstones and participated in various in vivo experiments; all authors read and approved the manuscript.
Institutional review board statement: The study was approved by the Ethics Committee of Seoul St Mary’s hospital, the Catholic University of Korea (IRB code: KC18TESI0103).
Institutional animal care and use committee statement: This animal study was approved by the Institutional Animal Care and Use Committee of the Clinical Research Institute at Daejeon St. Mary’s Hospital at the Catholic University of Korea (IRB No. CMCDJ-AP-2016-004).
Conflict-of-interest statement: All the Authors have no conflict of interest related to the manuscript; Authors got grant from Catholic Medical Center Research Foundation.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Say-June Kim, MD, PhD, Professor, Surgeon, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, South Korea. sayjunekim@gmail.com
Telephone: +82-10-87737616 Fax: +82-2-5350070
Received: July 2, 2019
Peer-review started: July 2, 2019
First decision: August 2, 2019
Revised: August 19, 2019
Accepted: September 11, 2019
Article in press: September 11, 2019
Published online: October 21, 2019
BACKGROUND
The use of methyl-tertiary butyl ether (MTBE) to dissolve gallstones has been limited due to concerns over its toxicity and the widespread recognition of the safety of laparoscopic cholecystectomy. The adverse effects of MTBE are largely attributed to its low boiling point, resulting in a tendency to evaporate. Therefore, if there is a material with a higher boiling point and similar or higher dissolubility than MTBE, it is expected to be an attractive alternative to MTBE.
AIM
To determine whether tert-amyl ethyl ether (TAEE), an MTBE analogue with a relatively higher boiling point (102 °C), could be used as an alternative to MTBE in terms of gallstone dissolubility and toxicity.
METHODS
The in vitro dissolubility of MTBE and TAEE was determined by measuring the dry weights of human gallstones at predetermined time intervals after placing them in glass containers with either of the two solvents. The in vivo dissolubility was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after the direct infusion of each solvent into the gallbladder in both hamster models with cholesterol and pigmented gallstones.
RESULTS
The in vitro results demonstrated a 24 h TAEE-dissolubility of 76.7%, 56.5% and 38.75% for cholesterol, mixed, and pigmented gallstones, respectively, which represented a 1.2-, 1.4-, and 1.3-fold increase in dissolubility compared to that of MTBE. In the in vitro experiment, the 24 h-dissolubility of TAEE was 71.7% and 63.0% for cholesterol and pigmented gallstones, respectively, which represented a 1.4- and 1.9-fold increase in dissolubility compared to that of MTBE. In addition, the results of the cell viability assay and western blot analysis indicated that TAEE had a lower toxicity towards gallbladder epithelial cells than MTBE.
CONCLUSION
We demonstrated that TAEE has higher gallstone dissolubility properties and safety than those of MTBE. As such, TAEE could present an attractive alternative to MTBE if our findings regarding its efficacy and safety can be consistently reproduced in further subclinical and clinical studies.
Core tip: We developed a novel gallstone-dissolving agent, named tert-amyl ethyl ether (TAEE), a methyl-tertiary butyl ether (MTBE) analogue, with a relatively higher boiling point (102 °C). The in vitro results demonstrated a 24 h TAEE-dissolubility of 76.7%, 56.5% and 38.75% for cholesterol, mixed, and pigmented gallstones, respectively, which represented a 1.2-, 1.4-, and 1.3-fold increase in dissolubility compared to that of MTBE. In the in vivo experiment, TAEE showed a 1.4- and 1.9-fold higher dissolubility for cholesterol and pigmented gallstones than MTBE. As such, TAEE could present an attractive alternative to MTBE if further clinical studies validate its efficacy and safety.
