Polyhexamethyleneguanidine Phosphate-Induced Cytotoxicity in Liver Cells Is Alleviated by Tauroursodeoxycholic Acid (TUDCA) via a Reduction in Endoplasmic Reticulum Stress
Polyhexamethyleneguanidine phosphate (PHMG-P) is a widely used polymeric antimicrobial agent known to induce significant pulmonary toxicity. Several studies have reported that the liver also can be a target organ of polyhexamethyleneguanidine (PHMG) toxicity, but the exact effect of this compound on...
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MDPI AG
2019-09-01
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| Reeks: | Cells |
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| Online toegang: | https://www.mdpi.com/2073-4409/8/9/1023 |
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| author | Sou Hyun Kim Doyoung Kwon Seunghyun Lee Sung Hwan Ki Hye Gwang Jeong Jin Tae Hong Yun-Hee Lee Young-Suk Jung |
| author_facet | Sou Hyun Kim Doyoung Kwon Seunghyun Lee Sung Hwan Ki Hye Gwang Jeong Jin Tae Hong Yun-Hee Lee Young-Suk Jung |
| author_sort | Sou Hyun Kim |
| collection | DOAJ |
| description | Polyhexamethyleneguanidine phosphate (PHMG-P) is a widely used polymeric antimicrobial agent known to induce significant pulmonary toxicity. Several studies have reported that the liver also can be a target organ of polyhexamethyleneguanidine (PHMG) toxicity, but the exact effect of this compound on liver cells is not well understood. To identify the mechanism of PHMG hepatotoxicity, HepG2 cells were exposed to PHMG-P for 72 h. The cell viability was significantly decreased by PHMG-P in a time- and concentration-dependent manner. The mitochondrial membrane potential was markedly reduced by PHMG-P and the apoptotic signaling cascade was activated. The increases observed in C/EBP homologous protein (CHOP), p-IRE, and p-JNK levels in PHMG-P-treated cells indicated the induction of endoplasmic reticulum stress. To verify the role of ER stress in PHMG-P-induced cytotoxicity, HepG2 cells were pretreated with the chemical chaperone, tauroursodeoxycholic acid (TUDCA) and then co-treated with TUDCA and PHMG-P for 24 h. Interestingly, TUDCA inhibited PHMG-P-induced ER stress and cytotoxicity in a dose-dependent manner. The apoptotic cell death and mitochondrial depolarization were also prevented by TUDCA. The proteins involved in the apoptotic pathway were all normalized to their control levels in TUDCA-treated cells. In conclusion, the results suggest that PHMG-P induced significant cytotoxicity in liver cells and ER stress-mediated apoptosis, which may be an important mechanism mediating this hepatotoxicity. |
| first_indexed | 2024-03-12T19:29:49Z |
| format | Article |
| id | doaj.art-9e177710c7a543c6b51e9bf80cd77689 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T19:29:49Z |
| publishDate | 2019-09-01 |
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| series | Cells |
| spelling | doaj.art-9e177710c7a543c6b51e9bf80cd776892023-08-02T04:40:27ZengMDPI AGCells2073-44092019-09-0189102310.3390/cells8091023cells8091023Polyhexamethyleneguanidine Phosphate-Induced Cytotoxicity in Liver Cells Is Alleviated by Tauroursodeoxycholic Acid (TUDCA) via a Reduction in Endoplasmic Reticulum StressSou Hyun Kim0Doyoung Kwon1Seunghyun Lee2Sung Hwan Ki3Hye Gwang Jeong4Jin Tae Hong5Yun-Hee Lee6Young-Suk Jung7Lab of Molecular Toxicology, College of Pharmacy, Pusan National University, Busan 46241, KoreaDepartment of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158-2280, USALab of Molecular Toxicology, College of Pharmacy, Pusan National University, Busan 46241, KoreaCollege of Pharmacy, Chosun University, Gwangju 61452, KoreaCollege of Pharmacy, Chungnam National University, Daejeon 34134, KoreaCollege of Pharmacy, Chungbuk National University, Cheongju 28160, KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, KoreaLab of Molecular Toxicology, College of Pharmacy, Pusan National University, Busan 46241, KoreaPolyhexamethyleneguanidine phosphate (PHMG-P) is a widely used polymeric antimicrobial agent known to induce significant pulmonary toxicity. Several studies have reported that the liver also can be a target organ of polyhexamethyleneguanidine (PHMG) toxicity, but the exact effect of this compound on liver cells is not well understood. To identify the mechanism of PHMG hepatotoxicity, HepG2 cells were exposed to PHMG-P for 72 h. The cell viability was significantly decreased by PHMG-P in a time- and concentration-dependent manner. The mitochondrial membrane potential was markedly reduced by PHMG-P and the apoptotic signaling cascade was activated. The increases observed in C/EBP homologous protein (CHOP), p-IRE, and p-JNK levels in PHMG-P-treated cells indicated the induction of endoplasmic reticulum stress. To verify the role of ER stress in PHMG-P-induced cytotoxicity, HepG2 cells were pretreated with the chemical chaperone, tauroursodeoxycholic acid (TUDCA) and then co-treated with TUDCA and PHMG-P for 24 h. Interestingly, TUDCA inhibited PHMG-P-induced ER stress and cytotoxicity in a dose-dependent manner. The apoptotic cell death and mitochondrial depolarization were also prevented by TUDCA. The proteins involved in the apoptotic pathway were all normalized to their control levels in TUDCA-treated cells. In conclusion, the results suggest that PHMG-P induced significant cytotoxicity in liver cells and ER stress-mediated apoptosis, which may be an important mechanism mediating this hepatotoxicity.https://www.mdpi.com/2073-4409/8/9/1023ER stressPHMG-Pcytotoxicitylivertauroursodeoxycholic acid |
| spellingShingle | Sou Hyun Kim Doyoung Kwon Seunghyun Lee Sung Hwan Ki Hye Gwang Jeong Jin Tae Hong Yun-Hee Lee Young-Suk Jung Polyhexamethyleneguanidine Phosphate-Induced Cytotoxicity in Liver Cells Is Alleviated by Tauroursodeoxycholic Acid (TUDCA) via a Reduction in Endoplasmic Reticulum Stress Cells ER stress PHMG-P cytotoxicity liver tauroursodeoxycholic acid |
| title | Polyhexamethyleneguanidine Phosphate-Induced Cytotoxicity in Liver Cells Is Alleviated by Tauroursodeoxycholic Acid (TUDCA) via a Reduction in Endoplasmic Reticulum Stress |
| title_full | Polyhexamethyleneguanidine Phosphate-Induced Cytotoxicity in Liver Cells Is Alleviated by Tauroursodeoxycholic Acid (TUDCA) via a Reduction in Endoplasmic Reticulum Stress |
| title_fullStr | Polyhexamethyleneguanidine Phosphate-Induced Cytotoxicity in Liver Cells Is Alleviated by Tauroursodeoxycholic Acid (TUDCA) via a Reduction in Endoplasmic Reticulum Stress |
| title_full_unstemmed | Polyhexamethyleneguanidine Phosphate-Induced Cytotoxicity in Liver Cells Is Alleviated by Tauroursodeoxycholic Acid (TUDCA) via a Reduction in Endoplasmic Reticulum Stress |
| title_short | Polyhexamethyleneguanidine Phosphate-Induced Cytotoxicity in Liver Cells Is Alleviated by Tauroursodeoxycholic Acid (TUDCA) via a Reduction in Endoplasmic Reticulum Stress |
| title_sort | polyhexamethyleneguanidine phosphate induced cytotoxicity in liver cells is alleviated by tauroursodeoxycholic acid tudca via a reduction in endoplasmic reticulum stress |
| topic | ER stress PHMG-P cytotoxicity liver tauroursodeoxycholic acid |
| url | https://www.mdpi.com/2073-4409/8/9/1023 |
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