Cytokines in non-genotoxic hepatocarcinogenesis

Many toxicants can cause liver injury. Some, such as diethylnitrosamine, are genotoxic and act principally by damaging DNA (1). A second more diverse group cause liver injury but are non-genotoxic (2). Despite differences in the primary target, genotoxic and non-genotoxic hepatotoxicants frequently cause tumours in the liver of experimental rats and mice (1,2). This review is concerned with evaluating the hypothesis that cytokines may play a role in mediating the biological effects of liver non-genotoxic carcinogens. Non-genotoxic liver toxicants constitute a diverse group of chemicals. Some, such as carbon tetrachloride (3), cause acute liver injury followed by regenerative hyperplasia, whereas others cause proliferation without identifiable tissue damage. The latter group includes barbiturate drugs such as phenobarbitone (PB) (4), dioxins such as 2,3,7,8-tetrachlorodibenzo-pdioxin (5,6) and the largest group, the peroxisome proliferators (PPs) (7). The induction of cell proliferation by toxicants that cause liver injury probably underpins their common ability to cause hepatocellular adenomas and carcinomas after prolonged exposure (8). During chemical-induced carcinogenesis, the tightly controlled balance that exists normally in tissues between cell growth and cell death is disrupted (9–11). Rodent hepatocarcinogenesis in response to PPs is preceded by liver enlargement due to hepatocyte hypertrophy and induction of cell proliferation coupled with suppression of hepatocyte apoptosis (7,12,13). The ability of barbiturates such as PB to stimulate hepatocyte DNA synthesis in vivo has also been demonstrated (14). The capacity of non-genotoxic liver carcinogens to perturb both sides of the growth equation between cell gain and cell loss can be modelled in vitro using hepatocytes prepared from rats or mice. In such models, PPs such as nafenopin can suppress spontaneous apoptosis (15–17) and also that induced by diverse stimuli, including transforming growth factor-β1. Interleukin (IL)-1 can act alongside TNFα to play a role in inflammation (18) and is implicated in the regulation of hepatic lipid metabolism (19), ligation of Fas or DNA damage (20). Thus, non-genotoxic carcinogens may