Genotoxic and antigenotoxic effects of galangin

Abstract

a common toxicity pathway. The initiating event is activation of the constitutive androstane receptor (CAR). This stimulates increased DNA replication and hepatocellular proliferation. Following prolonged exposure, this pro-proliferativemilieu combined with suppression of apoptosis promotes the growth and progression of spontaneously transformed cells, eventually producing hepatocellular adenomas. The ability of CCZ to elicit these key events in vivo was confirmed bymeasuring cytochrome P450 induction as a surrogate for CAR activation and replicative DNA synthesis to assess hepatocellular proliferation. In addition, the absolute requirement for CAR activation was demonstrated using CAR null mice. The following alternative MOAs for tumor formation were evaluated and excluded: genotoxicity, aryl-hydrocarbon receptor, peroxisome-proliferator activated receptor-alpha, oestrogen receptor, and cytotoxicity and subsequent regenerative growth. The lackof human relevance for theproposedMOAwasassessed by comparing the effects of CCZ on primary cultures of mouse and human hepatocytes. Treatment of mouse hepatocytes with CCZ resulted in CYP450 induction and replicativeDNA synthesis. In contrast, treatment of humanhepatocyteswith CCZ resulted in CYP450 induction, but not replicative DNA synthesis, indicating a qualitative species difference in response to CAR activation. The lack of proliferative response in humanhepatocytesmeans it is reasonable to conclude that CCZ is not hepatotumourgenic in humans.