Promotion of hepatocarcinogenesis in humans and animal models

• Published in: Archives of toxicology 2008-09, Vol.82 (9), p.623-631
• Main Authors: Köhle, Christoph, Schwarz, Michael, Bock, Karl Walter
• Format: Article
• Language: English
• Subjects: Alcoholism and acute alcohol poisoning; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens; Carcinogens - toxicity; Chemical agents; Disease Models, Animal; Environmental Health; Ethanol; Gastroenterology. Liver. Pancreas. Abdomen; Genotoxicity and Carcinogenicity; Hepatocytes - drug effects; Hepatocytes - pathology; Human subjects; Humans; Laboratory animals; Liver Neoplasms - chemically induced; Liver Neoplasms, Experimental - chemically induced; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Toxicology; Tumors
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-007-0273-7

Risk assessment based on rodent carcinogenicity data depends on the assumption of similarity between rodents and humans. While this assumption is conceivable in the case of genotoxic initiating carcinogens, considerable species differences have been observed with nongenotoxic tumor promoters. This heterogeneous group of agents increases the probability of cancer by stimulating selection and clonal expansion of cells transformed during tumor initiation. Since tumor promoters differentially affect normal tissue and preneoplastic cell clones, their action cannot be discussed without knowledge of persistent genomic and epigenetic alterations occurring during initiation and formation of preneoplastic cells. Chemical carcinogenesis, and in particular, tumor promotion, is known to be tissue specific. We focus on hepatocarcinogenesis in humans and in animal models and emphasize two different modes of action: (1) chronic cytotoxicity leading to promotion of liver carcinogenesis in both humans and animal models; (2) sustained activation of orphan receptors such as CAR, PPARα and Ah receptor leading to promotion of rodent but probably not human hepatocarcinogenesis. Further studies on the different modes of action may help to avoid overestimation of the risk of liver tumor promotion.