Brief Article
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World J Hepatol. Jul 27, 2013; 5(7): 379-386
Published online Jul 27, 2013. doi: 10.4254/wjh.v5.i7.379
Effect of dichloromethylene diphosphonate on liver regeneration following thioacetamide-induced necrosis in rats
Mirandeli Bautista, María Ángeles Gómez del Rio, Juana Benedí, María Isabel Sánchez-Reus, José A Morales-González, Ana María Téllez-López, Maricela López-Orozco
Mirandeli Bautista, Ana María Téllez-López, Maricela López-Orozco, Área Académica de Farmacia, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca, Hidalgo, CP 42000, México
María Ángeles Gómez del Rio, Juana Benedí, Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Ciudad Universitaria, Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain
María Isabel Sánchez-Reus, Departamento de Farmacología, Facultad de Farmacia, Ciudad Universitaria, Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain
José A Morales-González, Escuela Superior de Medicina, Instituto Politécnico Nacional, México City, CP 11340, México
Author contributions: All authors contributed equally to conducting the research and writing the paper.
Correspondence to: Dr. Mirandeli Bautista, Área Académica de Farmacia, Instituto de Ciencias de la Salud,Universidad Autónoma del Estado de Hidalgo, Abasolo N. 600, Colonia Centro, Pachuca, Hidalgo, CP 42000, México. mirandeli@hotmail.com
Telephone: +7-71-7172000 Fax: +7-71-7172000
Received: March 30, 2013
Revised: June 17, 2013
Accepted: June 18, 2013
Published online: July 27, 2013
Abstract

AIM: To study the effect of dichloromethylene diphosphonate (DMDP), a selective Kupffer cell toxicant in reference to liver damage and postnecrotic liver regeneration in rats induced by sublethal dose thioacetamide (TA).

METHODS: Rats, intravenously (iv) pre-treated with a single dose of DMDP (10 mg/kg), were intraperitoneally (ip) injected with TA 6.6 mmol/kg (per 500 mg/kg body weight). Hepatocytes were isolated from rats at 0, 24, 48 and 72 h following TA intoxication and blood and liver samples were obtained. To evaluate the mechanisms involved in the postnecrotic regenerative state, DNA distribution and ploidy time course were assayed in isolated hepatocytes. Circulating cytokine tumor necrosis factor-alpha (TNF-α) was assayed in serum and determined by reverse transcriptase-polymerase chain reaction in liver extract.

RESULTS: The effect of DMDP induced noticeable changes in postnecrotic regeneration, causing an increased percentage of hepatocytes in the cell cycle S phase. The increase at 24 h in S1 population in rats pretreated with DMDP + TA was significantly (P < 0.05) different compared with that of the TA group (18.07% vs 8.57%). Hepatocytes increased their proliferation as a result of these changes. Also, TNF-α expression and serum level were increased in rats pre-treated with DMDP. Thus, DMDP pre-treatment reduced TA-induced liver injury and accelerated postnecrotic liver regeneration.

CONCLUSION: These results demonstrate that Kupffer cells are involved in TA-induced liver, as well as in postnecrotic proliferative liver states.

Keywords: Dichloromethylene diphosphonate, Kupffer cells, Thioacetamide, Hepatotoxicity, Cell cycle

Core tip: Over the last 20 years, liposomes, useful models for cell membranes, have become a powerful research tool whose study has resulted in many advances in cell physiology. When encapsulated in liposomes, dichloromethylene diphosphonate, a selective Kupffer cell toxicant, completely eliminates large Kupffer cells from the liver, allowing us to elucidate the role of these macrophages in total damage induced by hepatotoxic compounds such as thioacetamide.