Vancomycin pretreatment attenuates acetaminophen-induced liver injury through 2-hydroxybutyric acid

Ningning Zheng; Yu Gu; Ying Hong; Lili Sheng; Linlin Chen; Feng Zhang; Jie Hou; Weidong Zhang; Zean Zhang; Wei Jia; Houkai Li

doi:10.1016/j.jpha.2019.11.003

Vancomycin pretreatment attenuates acetaminophen-induced liver injury through 2-hydroxybutyric acid

J Pharm Anal. 2020 Dec;10(6):560-570. doi: 10.1016/j.jpha.2019.11.003. Epub 2019 Nov 6.

Authors

Ningning Zheng¹, Yu Gu¹, Ying Hong¹, Lili Sheng¹, Linlin Chen¹, Feng Zhang¹, Jie Hou², Weidong Zhang^{1

3}, Zean Zhang⁴, Wei Jia^{5

6}, Houkai Li¹

Affiliations

¹ Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
² College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
³ School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
⁴ Center for Drug Safety Evaluation and Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
⁵ University of Hawaii Cancer Center, Honolulu, HI, 96813, USA.
⁶ Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.

Abstract

Liver injury caused by acetaminophen (AP) overdose is a leading public health problem. Although AP-induced liver injury is well recognized as the formation of N-acetyl-p-benzoquinone (NAPQI), a toxic metabolite of AP, resulting in cell damage, emerging evidence indicates that AP-induced liver injury is also associated with gut microbiota. However, the gut microbiota-involved mechanism remains largely unknown. In our study, we found that vancomycin (Vac) pretreatment (100 mg/kg, twice a day for 4 days) attenuated AP-induced liver injury, altered the composition of gut microbiota, and changed serum metabolic profile. Moreover, we identified Vac pretreatment elevated cecum and serum 2-hydroxybutyric acid (2-HB), which ameliorated AP-induced cell damage and liver injury in mice by reducing AP bioavailability and elevating GSH levels. Our current results revealed the novel role of 2-HB in protecting AP-induced liver injury and add new evidence for gut microbiota in affecting AP toxicity.

Keywords: 2-Hydroxybutyric acid; Acetaminophen; Gut microbiota; Liver injury; Vancomycin; revealed.