AOPs Including This Stressor
Events Including This Stressor
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Constitutive androstane receptor activation leading to hepatocellular adenomas and carcinomas in the mouse and the rat
Metofluthrin produced increased liver tumors in male and female Wistar rats at dose levels of 900 and 1800 ppm in the diet for 2 years (Deguchi et al., 2009). As shown in Table 5 of the AOP for CAR-mediated rodent liver tumors, dose-concordant data supporting all of the Key Events and/or Associative Events in the AOP for CAR have been demonstrated with metofluthrin (Deguchi et al., 2009; Yamada et al., 2009). Therefore, there is Strong evidence for metofluthrin as an AOP stressor for the CAR-mediated formation of rat liver tumors.
There is no evidence text for this event.
1. The hepatic gene expression profiles of male rats administered 3600 ppm metofluthrin in the diet for one week had similar gene expression profiles to those of male rats administered 1000 ppm NaPB (a known CAR activator) for one week, including the modulation of xenobiotic metabolism genes. For example, a statistically-significant, dose-dependent induction of the mRNA levels of Cyp2b1/2 and Cyp3a1 was observed in the livers of male and female rats administered metofluthrin in the diet for one week (Deguchi et al., 2009; Yamada et al., 2009). Additional experiments used RNA interference (RNAi) where CAR-specific small interfering RNA (siRNA) was co-incubated along with metofluthrin. Exposure of rat hepatocytes to metofluthrin plus the CAR siRNA in vitro resulted in a statistically significant reduction in the Cyp2b1 mRNA levels compared to hepatocytes treated with metofluthrin without CAR knockdown (Deguchi et al., 2009).