Prevention of rat liver fibrosis and carcinogenesis by coffee and caffeine

Highlights

• Conventional coffee or caffeine intake reduced the liver collagen content and collagen I mRNA levels.

• Instant coffee or caffeine intake inhibited the development of hepatocellular pre-neoplastic and neoplastic lesions.

• Coffee beverages are potential functional food against liver fibrosis and carcinogenesis.

Abstract

Coffee has been inversely related to the incidence of human liver disease; however, whether caffeine is the component responsible for the beneficial effects of coffee remains controversial. This study evaluated the beneficial effects of coffee or caffeine in a medium-term bioassay for rat liver fibrosis/carcinogenesis induced by diethylnitrosamine (DEN) and carbon tetrachloride (CCl₄). One week after the DEN injection, the groups started to receive conventional coffee, instant coffee or 0.1% caffeine ad libitum for 24 weeks. The groups receiving conventional coffee or caffeine presented a significant reduction in collagen content and mRNA expression of collagen I. The groups receiving instant coffee or caffeine had a significant reduction in the size and area of pre-neoplastic lesions and in the mean number of neoplastic lesions. A significant increase in liver bax protein levels was observed in the groups receiving instant coffee or caffeine as compared to the control group. These data indicate that the most pronounced hepatoprotective effect against fibrosis was observed in the groups receiving conventional coffee and 0.1% caffeine, and the greatest effects against liver carcinogenesis were detected in the groups receiving instant coffee and 0.1% caffeine.

Introduction

The majority of human chronic liver diseases follow a common pathway that is initiated by inflammation leading to fibrosis and cirrhosis, which are associated with high indexes of morbidity and mortality worldwide (Wanless, 2004, Lim and Kim, 2008, Hernandez-Gea and Friedman, 2011). Liver fibrosis and cirrhosis are consequences of a continuous regenerative process in response to sustained noxious stimuli, such as chronic hepatitis B and C infections or chronic alcohol abuse (Wanless, 2004, Lim and Kim, 2008, Hernandez-Gea and Friedman, 2011). Cirrhosis is an irreversible and terminal step in the fibrotic process, characterised by impairment of hepatic architecture and function (Wanless, 2004, Lim and Kim, 2008, Fallowfield et al., 2006, Kisseleva and Brenner, 2007, Hernandez-Gea and Friedman, 2011).

The fibrotic/cirrhotic process leads to the formation of hepatic nodules and the accumulation of extracellular matrix proteins, mainly collagens I and III, proteoglycans and glycoproteins (Wanless, 2004, Kisseleva and Brenner, 2007, Hernandez-Gea and Friedman, 2011). This process starts with a cascade of events leading to recruitment of inflammatory cells and activation of collagen-producing cells, including hepatic stellate cells (Kisseleva and Brenner, 2007, Hernandez-Gea and Friedman, 2011). Because chronic fibrosis/cirrhosis can lead to the development of hepatocellular carcinoma, there have been increased efforts to develop preventive strategies to inhibit the progression of fibrosis/cirrhosis and consequently, tumour development (Fallowfield et al., 2006, Kisseleva and Brenner, 2007, Hoshida et al., 2012).

Coffee is one of the most popular and highly consumed beverages worldwide, and its moderate intake has been considered to be safe and beneficial for human health (Heckman et al., 2010, Butt and Sultan, 2011). Consumption of more than three cups of coffee per day has been inversely related to the incidence of non-alcoholic fatty liver disease, fibrosis/cirrhosis and hepatocellular carcinoma development in subjects with or without hepatitis B and/or C infection (Klatsky et al., 2006, Bravi et al., 2007, Catalano et al., 2010, Modi et al., 2010, Costentin et al., 2011, Leung et al., 2011). Mechanistic studies have suggested that coffee, caffeine and/or diterpenes cafestol and kahweol intake are beneficial due to antioxidant properties including increase in glutathione levels and modifying effects on phase I-activating and phase II-detoxifying enzymes, leading to protection against the development of liver diseases (Cadden et al., 2007, Lee et al., 2007, Huber et al., 2008, Cavin et al., 2008, Tao et al., 2008, Boettler et al., 2011). However, whether this protection is exerted by coffee per se or by specific components, such as caffeine, chlorogenic acid and the diterpenes cafestol and kahweol, remains controversial (Cadden et al., 2007, Huber et al., 2008, Cavin et al., 2008, Tao et al., 2008, Boettler et al., 2011). Experimental studies have suggested that the intake of instant coffee, conventional coffee, caffeine or the diterpenes cafestol and kahweol can reduce hepatotoxicant-induced liver fibrosis in male rats and mice (Ozercan et al., 2006, Lee et al., 2007, Shi et al., 2010, Shin et al., 2010, Moreno et al., 2011, Furtado et al., 2012).

A few in vivo studies attempted to elucidate the modifying effects of coffee or caffeine intake on the process of chemically-induced liver carcinogenesis (Hasegawa et al., 1995, Hosaka et al., 2001, Silva-Oliveira et al., 2010, Fujise et al., 2012). In addition, the available investigations are difficult to compare due to the different doses and types of coffee preparations adopted. Thus, the present study aimed to elucidate the beneficial effects of different coffee beverages (conventional and instant) and caffeine alone against chemically induced fibrosis and carcinogenesis in the liver of male Wistar rats.