High dietary levels of the non-genotoxic synthetic
pyrethroid momfluorothrin increased the incidence of hepatocellular
tumors in male and female Wistar rats. Mechanistic studies have demonstrated that the mode of action (MOA) for
momfluorothrin-induced hepatocellular
tumors is
constitutive androstane receptor (CAR)-mediated. In the present study, to evaluate the potential human carcinogenic risk of
momfluorothrin, the effects of
momfluorothrin (1-1,000 µM) and a major metabolite Z-CMCA (5-1,000 µM) on hepatocyte replicative
DNA synthesis and CYP2B
mRNA expression were examined in cultured rat and human hepatocyte preparations. The effect of
sodium phenobarbital (NaPB), a prototypic rodent hepatocarcinogen with a CAR-mediated MOA, was also investigated. Human
hepatocyte growth factor (hHGF) produced a concentration-dependent increase in replicative
DNA synthesis in rat and human hepatocytes. However, while NaPB and
momfluorothrin increased replicative
DNA synthesis in rat hepatocytes, NaPB,
momfluorothrin and Z-CMCA did not increase replicative
DNA synthesis in human hepatocytes. NaPB,
momfluorothrin and Z-CMCA increased
CYP2B1/2
mRNA levels in rat hepatocytes. NaPB and
momfluorothrin also increased
CYP2B6 mRNA levels in human hepatocytes. Overall, while
momfluorothrin and NaPB activated CAR in cultured human hepatocytes, neither chemical increased replicative
DNA synthesis. Furthermore, to confirm whether the findings observed in vitro were also observed in vivo, a humanized chimeric mouse study was conducted. Replicative
DNA synthesis was not increased in human hepatocytes of chimeric mice treated with
momfluorothrin or its close structural analogue
metofluthrin. As human hepatocytes are refractory to the mitogenic effects of
momfluorothrin, in contrast to rat hepatocytes, the data support the hypothesis that the MOA for
momfluorothrin-induced rat liver
tumor formation is not relevant for humans.