Protective effect of ALDH2 against cyclophosphamide-induced acute hepatotoxicity via attenuating oxidative stress and reactive aldehydes

Xiaoxuan Zhai; Zhenxiao Zhang; Wenwen Liu; Baoshan Liu; Rui Zhang; Wenjun Wang; Wen Zheng; Feng Xu; Jiali Wang; Yuguo Chen

doi:10.1016/j.bbrc.2018.03.041

Protective effect of ALDH2 against cyclophosphamide-induced acute hepatotoxicity via attenuating oxidative stress and reactive aldehydes

Biochem Biophys Res Commun. 2018 Apr 30;499(1):93-98. doi: 10.1016/j.bbrc.2018.03.041. Epub 2018 Mar 21.

Authors

Xiaoxuan Zhai¹, Zhenxiao Zhang², Wenwen Liu¹, Baoshan Liu¹, Rui Zhang¹, Wenjun Wang¹, Wen Zheng¹, Feng Xu¹, Jiali Wang³, Yuguo Chen⁴

Affiliations

¹ Department of Emergency Medicine and Chest Pain Center, Qilu Hospital, Shandong University, Jinan, China; Institute of Emergency and Critical Care Medicine, Shandong University, Jinan, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China.
² Department of Emergency Medicine and Chest Pain Center, Qilu Hospital, Shandong University, Jinan, China; The Affiliated Hospital of Qingdao University, Qingdao, China; Institute of Emergency and Critical Care Medicine, Shandong University, Jinan, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China.
³ Department of Emergency Medicine and Chest Pain Center, Qilu Hospital, Shandong University, Jinan, China; Institute of Emergency and Critical Care Medicine, Shandong University, Jinan, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China. Electronic address: wangjiali_2000@126.com.
⁴ Department of Emergency Medicine and Chest Pain Center, Qilu Hospital, Shandong University, Jinan, China; Institute of Emergency and Critical Care Medicine, Shandong University, Jinan, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China. Electronic address: chen919085@sdu.edu.cn.

PMID: 29524404
DOI: 10.1016/j.bbrc.2018.03.041

Abstract

Cyclophosphamide (CY) is a widely used chemotherapeutic agent that is associated with severe side effects, such as hepatotoxicity and nephrotoxicity. However, the extent, mechanisms and potential prevention and treatment strategies of CY-induced acute hepatotoxicity and nephrotoxicity are largely unknown. In this study, we determined the existence and extent of CY-induced acute hepatotoxicity and nephrotoxicity, and demonstrated the effect of ALDH2 on CY-induced acute tissue toxicity and related mechanisms. Adult male C57BL/6J (wide-type, WT) and ALDH2^-/- (KO) mice were divided into four groups: WT, WT + CY, KO + CY and WT + CY + Alda-1. Biochemical analysis showed that plasma ALT was increased by 35.8% in KO + CY group and decreased by 21.1% in WT + CY + Alda-1 group compared to WT + CY group (P < 0.05, respectively). However, there was no significant difference among WT, WT + CY and KO + CY groups regarding plasma renal marker enzymes, including blood urea nitrogen (BUN), creatinine and cystatin C (CysC). Levels of reactive oxygen species (ROS) and toxic aldehydes (acrolein, 4-hydroxynonenol and malondialdehyde) were increased significantly in KO + CY group and decreased significantly in WT + CY + Alda-1 group compared to WT + CY group (P < 0.05, respectively). These findings demonstrate that CY could induce acute hepatotoxicity without nephrotoxicity, and ALDH2 plays a protective role in CY-induced acute hepatotoxicity. The underlying mechanisms are associated with attenuating oxidative stress and detoxifying reactive aldehydes.

Keywords: ALDH2; Cyclophosphamide; Hepatotoxicity; Oxidative stress; Reactive aldehydes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acrolein / metabolism
Alanine Transaminase / blood
Aldehyde Dehydrogenase, Mitochondrial / deficiency
Aldehyde Dehydrogenase, Mitochondrial / genetics*
Aldehydes / metabolism
Animals
Aspartate Aminotransferases / blood
Blood Urea Nitrogen
Chemical and Drug Induced Liver Injury / enzymology
Chemical and Drug Induced Liver Injury / etiology
Chemical and Drug Induced Liver Injury / genetics*
Chemical and Drug Induced Liver Injury / prevention & control*
Creatinine / blood
Cyclophosphamide / toxicity*
Cystatin C / blood
Gene Expression Regulation
Kidney / enzymology*
Kidney / pathology
L-Lactate Dehydrogenase / blood
Liver / enzymology*
Liver / pathology
Male
Malondialdehyde / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxidative Stress
Reactive Oxygen Species / metabolism

Substances

Aldehydes
Cystatin C
Reactive Oxygen Species
Malondialdehyde
Acrolein
Cyclophosphamide
Creatinine
L-Lactate Dehydrogenase
ALDH2 protein, mouse
Aldehyde Dehydrogenase, Mitochondrial
Aspartate Aminotransferases
Alanine Transaminase
4-hydroxy-2-nonenal