Chapter 10: Conazoles and Cancer: A Review

This chapter reviews the biochemical, molecular, toxicological and toxicogenomic effects of conazoles with an emphasis on their contribution to the tumorigenic activities of these agents in experimental systems. The development of conazoles as inhibitors of fungal CYP51 for pharmaceutical applications and their mechanism of the inhibition of CYP51 is discussed. The biochemical and biological effects of conazoles are reviewed, including inhibition of CYPs, induction of CYPs, increased liver weights, hepatic hypertrophy and hepatic cell proliferation and effects on serum cholesterol and triglyceride levels. A summary of the genotoxicity and tumorigenic effects of conazoles is presented and analyses of toxicogenomic studies in mice and rats (focusing on liver and thyroid tissues) are summarized. A mode of carcinogenic action for the induction of liver cancer in mice by propiconazole is presented. This mode of action is primarily based on the ability of propiconazole to induce a group of CYPs and its ability to inhibit CYP51. A series of key events that lead to the induction of hepatocellular adenomas and carcinomas is presented. The relevance of many of these key events identified in mice to the human situation is discussed. Finally, the toxicologic and genomic data on the modes of action of phenobarbital and propiconazole are compared and discussed.