Effect of cimetidine, ranitidine, famotidine and omeprazole on hepatocyte proliferation in vitro

Abstract

Recently reports have indicated that both cimetidine and ranitidine delay cell proliferation in rats following 7W/c partial hepatectomy and result in an increased mortality following this procedure. The present study was designed to determine whether three Hz blocking agents (cimetidine, ranitidine, famotidine) and a new, powerful antisecretory drug (omeprazole) specifically influence hepatocyte proliferation in primary culture. Hepatocytes were isolated from livers of normal male rats by the standard collagenase perfusion technique. Hepatic DNA synthesis and percent of labelled nuclei were determined after 48 h incubation. Hepatocytes in culture were incubated with the Hz blocking agents and omeprazole or with different concentrations of serum obtained from shamoperated or 70% hepatectomized rats treated or not with the same agents. Rats were injected intraperitoneally at 8:00 a.m. on two consecutive days. In hepatectomized rats, the first dose was injected at 1'\:00 a.m. immediately after surgery, the second, 24 h later. The serum of sham-operated or 70O/C hepatectomized rats that did not receive drugs served as control. No changes in DNA synthesis, percentage of labelled nuclei and transaminase were detected when the agents were added to the hepatocytes in culture at concentrations within the effective pharmacological dosage and 30 times higher. Similarly, no changes in these parameters were obtained when different concentrations of serum obtained from sham-operated rats treated with Hz blocking agents or omeprazole were added to the basal culture medium. However, a significant inhibition of DN A synthesis and of percentage of labelled nuclei was observed when hepatocytes were incubated in the presence of serum from 70o/r hepatectomized rats that had been treated with cimetidine or with ranitidine. The serum of 7fFX hepatectomized rats treated with famotidine and omeprazole had no effect on hepatocyte proliferation in vitro. No effect on transaminase was found in these conditions.

Gastric Mucosal Cell Proliferation in Ethanol-Induced Chronic Mucosal Injury Is Related to Oxidative Stress and Lipid Peroxidation in Rats

“…Although the mechanism has not been clarified, H 2 RA-induced changes in liver blood flow had no influence on their deleterious action on regenerating liver. Interestingly, both cimetidine and ranitidine had no effect on DNA synthesis or rate of mitosis when added to a hepatocyte culture at concentrations within the effective pharmacological dosage, and even 30 times higher, but serum from hepatectomized animals treated with these H 2 RA did inhibit in vitro proliferation of hepatocytes (Francavilla et al, 1989). These findings suggest that metabolite by-products of H 2 RA might affect the concentration of hormonal and growth factors in animals with regenerating liver.…”

Trovafloxacin-induced replication stress sensitizes HepG2 cells to tumor necrosis factor-alpha-induced cytotoxicity mediated by extracellular signal-regulated kinase and ataxia telangiectasia and Rad3-related

“…TVX decreased the rate of cell proliferation and caused cell cycle arrest (Figures 1 and 2), as has been reported for TVX treatment of several cell types in vitro (Holtom et al 2000; Thadepalli et al 2005; Zakeri et al 2000). Interestingly, several other drugs that cause IDILI inhibit cell proliferation in vitro as well (Basta-Kaim et al 2006; Chennamaneni et al 2012; Francavilla et al 1989; Rajabalian et al 2009). …”

“…It is of interest, however that several other drugs associated with human IDILI induce cell cycle arrest in vitro (Basta-Kaim et al 2006; Chennamaneni et al 2012; Francavilla et al 1989; Rajabalian et al 2009). Our results suggest that interference of DNA replication by certain drugs might act as a first insult that sensitizes cells to a secondary insult from cytokines such as TNF that are produced by an activated immune system.…”

Efeito do omeprazol e do pantoprazol sobre a regeneração hepática após hepatectomia parcial em ratos

“…Um estudo com hepatócitos in vitro mostrou que o omeprazol atua como um inibidor das mono-oxigenases do citocromo P-450 11 . Já Francavilla et al (1989) 12 observaram que, nas mesmas condições de estudo, não afetou a proliferação dos hepatócitos e a estimulou após administrações repetidas da substância.…”