Association of NAT2 promoter hypermethylation with susceptibility to hepatotoxicity due to antituberculosis drugs and biomarker potential
Abstract This study aimed to determine whether promoter methylation of N-acetyltransferase 2 (NAT2), a metabolic enzyme responsible for drug metabolism and detoxification, was correlated with clinical parameters indicating anti-tuberculosis drug-induced liver injury (ATDILI) in tuberculosis patients...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-03-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-95050-6 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850208627223166976 |
|---|---|
| author | Jiraphun Jittikoon Wacharapol Saengsiwaritt Noppadol Chanhom Usa Chaikledkaew Sukanya Wattanapokayakit Surakameth Mahasirimongkol Wanvisa Udomsinprasert |
| author_facet | Jiraphun Jittikoon Wacharapol Saengsiwaritt Noppadol Chanhom Usa Chaikledkaew Sukanya Wattanapokayakit Surakameth Mahasirimongkol Wanvisa Udomsinprasert |
| author_sort | Jiraphun Jittikoon |
| collection | DOAJ |
| description | Abstract This study aimed to determine whether promoter methylation of N-acetyltransferase 2 (NAT2), a metabolic enzyme responsible for drug metabolism and detoxification, was correlated with clinical parameters indicating anti-tuberculosis drug-induced liver injury (ATDILI) in tuberculosis patients and might emerge as an ATDILI biomarker. NAT2 promoter methylation in blood leukocyte of 102 tuberculosis patients (49 ATDILI cases and 53 non-ATDILI cases) and 100 healthy controls were quantified using quantitative real-time methylation-specific polymerase chain reaction. Compared to healthy volunteers, tuberculosis patients had significantly reduced NAT2 demethylation index. Compared with non-ATDILI patients, NAT2 demethylation index was significantly decreased in ATDILI patients. An independent association was found between lower NAT2 demethylation index and increased susceptibility to ATDILI. NAT2 demethylation index quantified after starting treatment within 1–7 days was negatively correlated with serum aminotransferases measured within 8–60 days of treatment. ROC curve analysis uncovered that NAT2 demethylation index was found to be a more sensitive and specific biomarker for ATDILI when compared to serum aminotransferases measured following treatment initiation within 1–7 days. Kaplan–Meier analysis unveiled a notable association between lower NAT2 demethylation index and a higher incidence of ATDILI in tuberculosis patients, as confirmed by Cox regression analysis while accounting for confounding variables. A reduction in NAT2 demethylation index could reflect ATDILI progression and potentially be used as a new, specific biomarker for ATDILI. |
| format | Article |
| id | doaj-art-4f08fdefc7b54769a19ac3f4af7d712a |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-4f08fdefc7b54769a19ac3f4af7d712a2025-08-20T02:10:12ZengNature PortfolioScientific Reports2045-23222025-03-0115111110.1038/s41598-025-95050-6Association of NAT2 promoter hypermethylation with susceptibility to hepatotoxicity due to antituberculosis drugs and biomarker potentialJiraphun Jittikoon0Wacharapol Saengsiwaritt1Noppadol Chanhom2Usa Chaikledkaew3Sukanya Wattanapokayakit4Surakameth Mahasirimongkol5Wanvisa Udomsinprasert6Department of Biochemistry, Faculty of Pharmacy, Mahidol UniversityDepartment of Biochemistry, Faculty of Pharmacy, Mahidol UniversityDepartment of Biochemistry, Faculty of Pharmacy, Mahidol UniversitySocial and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol UniversityDivision of Genomic Medicine and Innovation Support, Department of Medical Sciences, Genomic Medicine Centre, Ministry of Public HealthDivision of Genomic Medicine and Innovation Support, Department of Medical Sciences, Genomic Medicine Centre, Ministry of Public HealthDepartment of Biochemistry, Faculty of Pharmacy, Mahidol UniversityAbstract This study aimed to determine whether promoter methylation of N-acetyltransferase 2 (NAT2), a metabolic enzyme responsible for drug metabolism and detoxification, was correlated with clinical parameters indicating anti-tuberculosis drug-induced liver injury (ATDILI) in tuberculosis patients and might emerge as an ATDILI biomarker. NAT2 promoter methylation in blood leukocyte of 102 tuberculosis patients (49 ATDILI cases and 53 non-ATDILI cases) and 100 healthy controls were quantified using quantitative real-time methylation-specific polymerase chain reaction. Compared to healthy volunteers, tuberculosis patients had significantly reduced NAT2 demethylation index. Compared with non-ATDILI patients, NAT2 demethylation index was significantly decreased in ATDILI patients. An independent association was found between lower NAT2 demethylation index and increased susceptibility to ATDILI. NAT2 demethylation index quantified after starting treatment within 1–7 days was negatively correlated with serum aminotransferases measured within 8–60 days of treatment. ROC curve analysis uncovered that NAT2 demethylation index was found to be a more sensitive and specific biomarker for ATDILI when compared to serum aminotransferases measured following treatment initiation within 1–7 days. Kaplan–Meier analysis unveiled a notable association between lower NAT2 demethylation index and a higher incidence of ATDILI in tuberculosis patients, as confirmed by Cox regression analysis while accounting for confounding variables. A reduction in NAT2 demethylation index could reflect ATDILI progression and potentially be used as a new, specific biomarker for ATDILI.https://doi.org/10.1038/s41598-025-95050-6N-Acetyltransferase 2 (NAT2)Promoter methylationAnti-tuberculosis drug-induced liver injuryTuberculosisBiomarker |
| spellingShingle | Jiraphun Jittikoon Wacharapol Saengsiwaritt Noppadol Chanhom Usa Chaikledkaew Sukanya Wattanapokayakit Surakameth Mahasirimongkol Wanvisa Udomsinprasert Association of NAT2 promoter hypermethylation with susceptibility to hepatotoxicity due to antituberculosis drugs and biomarker potential Scientific Reports N-Acetyltransferase 2 (NAT2) Promoter methylation Anti-tuberculosis drug-induced liver injury Tuberculosis Biomarker |
| title | Association of NAT2 promoter hypermethylation with susceptibility to hepatotoxicity due to antituberculosis drugs and biomarker potential |
| title_full | Association of NAT2 promoter hypermethylation with susceptibility to hepatotoxicity due to antituberculosis drugs and biomarker potential |
| title_fullStr | Association of NAT2 promoter hypermethylation with susceptibility to hepatotoxicity due to antituberculosis drugs and biomarker potential |
| title_full_unstemmed | Association of NAT2 promoter hypermethylation with susceptibility to hepatotoxicity due to antituberculosis drugs and biomarker potential |
| title_short | Association of NAT2 promoter hypermethylation with susceptibility to hepatotoxicity due to antituberculosis drugs and biomarker potential |
| title_sort | association of nat2 promoter hypermethylation with susceptibility to hepatotoxicity due to antituberculosis drugs and biomarker potential |
| topic | N-Acetyltransferase 2 (NAT2) Promoter methylation Anti-tuberculosis drug-induced liver injury Tuberculosis Biomarker |
| url | https://doi.org/10.1038/s41598-025-95050-6 |
| work_keys_str_mv | AT jiraphunjittikoon associationofnat2promoterhypermethylationwithsusceptibilitytohepatotoxicityduetoantituberculosisdrugsandbiomarkerpotential AT wacharapolsaengsiwaritt associationofnat2promoterhypermethylationwithsusceptibilitytohepatotoxicityduetoantituberculosisdrugsandbiomarkerpotential AT noppadolchanhom associationofnat2promoterhypermethylationwithsusceptibilitytohepatotoxicityduetoantituberculosisdrugsandbiomarkerpotential AT usachaikledkaew associationofnat2promoterhypermethylationwithsusceptibilitytohepatotoxicityduetoantituberculosisdrugsandbiomarkerpotential AT sukanyawattanapokayakit associationofnat2promoterhypermethylationwithsusceptibilitytohepatotoxicityduetoantituberculosisdrugsandbiomarkerpotential AT surakamethmahasirimongkol associationofnat2promoterhypermethylationwithsusceptibilitytohepatotoxicityduetoantituberculosisdrugsandbiomarkerpotential AT wanvisaudomsinprasert associationofnat2promoterhypermethylationwithsusceptibilitytohepatotoxicityduetoantituberculosisdrugsandbiomarkerpotential |