Metronidazole enhances steatosis-related early-stage hepatocarcinogenesis in high fat diet-fed rats through DNA double-strand breaks and modulation of autophagy

被引：11

作者：

Eguchi, Ayumi ^{[1
]}

Mizukami, Sayaka ^{[1
,2
]}

Nakamura, Misato ^{[1
]}

Masuda, Sousuke ^{[1
]}

Murayama, Hirotada ^{[1
]}

Kawashima, Masashi ^{[1
]}

Inohana, Mari ^{[1
]}

Nagahara, Rei ^{[1
]}

Kobayashi, Mio ^{[1
]}

Yamashita, Risako ^{[1
]}

Uomoto, Suzuka ^{[1
]}

Makino, Emi ^{[3
]}

Ohtsuka, Ryoichi ^{[3
]}

Takahashi, Naofumi ^{[3
]}

Hayashi, Shim-Mo ^{[4
]}

Maronpot, Robert R. ^{[5
]}

Shibutani, Makoto ^{[1
]}

Yoshida, Toshinori ^{[1
]}

机构：

[1] Tokyo Univ Agr & Technol, Fac Agr, Cooperat Dept Vet Med, Lab Vet Pathol, 3-5-8 Saiwai Cho, Fuchu, Tokyo 1838509, Japan

[2] Gifu Univ, United Grad Sch Vet Sci, Pathogenet Vet Sci, 1-1 Yanagido, Gifu, Gifu 5011193, Japan

[3] Inst Environm Toxicol, 4321 Uchimoriya Machi, Joso, Ibaraki 3030043, Japan

[4] San Ei Gen FFI Inc, Global Sci & Regulatory Affairs, 1-1-11 Sanwa Cho, Toyonaka, Osaka 5618588, Japan

[5] Maronpot Consulting LLC, 1612 Medfield Rd, Raleigh, NC 27607 USA

来源：

ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH | 2022年 / 29卷 / 01期

关键词：

gamma-H2AX; LC3; Metronidazole; NAFLD; p62; PPAR gamma; PRENEOPLASTIC LIVER FOCI; NONALCOHOLIC STEATOHEPATITIS; HEPATOCELLULAR-CARCINOMA; HEPATIC STEATOSIS; NUCLEAR RECEPTORS; ESCHERICHIA-COLI; INDUCTION; METABOLISM; EXPRESSION; MODEL;

D O I：

10.1007/s11356-021-15689-2

中图分类号：

X [环境科学、安全科学];

学科分类号：

08 ; 0830 ;

摘要：

Nonalcoholic fatty liver disease is a hepatic disorder with deposition of fat droplets and has a high risk of progression to steatosis-related hepatitis and irreversible hepatic cancer. Metronidazole (MNZ) is an antiprotozoal and antimicrobial agent widely used to treat patients infected with anaerobic bacteria and intestinal parasites; however, MNZ has also been shown to induce liver tumors in rodents. To investigate the effects of MNZ on steatosis-related early-stage hepatocarcinogenesis, male rats treated with N-nitrosodiethylamine following 2/3 hepatectomy at week 3 were received a control basal diet, high fat diet (HFD), or HFD containing 0.5% MNZ. The HFD induced obesity and steatosis in the liver, accompanied by altered expression of Pparg and Fasn, genes related to lipid metabolism. MNZ increased nuclear translocation of lipid metabolism-related transcription factor peroxisome proliferator-activated receptor gamma in hepatocytes, together with altered liver expression of lipid metabolism genes (Srebf1, Srebf2, Pnpla2). Furthermore, MNZ significantly increased the number of preneoplastic liver foci, accompanied by DNA double-strand breaks and late-stage autophagy inhibition, as reflected by increased levels of gamma-H2AX, LC3, and p62. Therefore, MNZ could induce steatosis-related hepatocarcinogenesis by inducing DNA double-strand breaks and modulating autophagy in HFD-fed rats.

引用

页码：779 / 789

页数：11

共 72 条

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