Piperonyl butoxide, alpha-[2-(2-butoxyethoxy)ethoxy]-4,5-methylenedioxy-2-propyltol uene, is a widely used
pesticide-synergist. Recently, results were reported indicating that
piperonyl butoxide is a hepatocarcinogen in rat. Since the underlying mechanism was not elucidated, we examined the effects on rat liver cells in detail. For this purpose male F344 rats were administered
piperonyl butoxide mixed in the diet at concentrations of 0 (negative control), 0.05, 0.2 or 2% for 2 days, 1, 2, and 4 weeks. As a positive control,
phenobarbital was administered to rats for up to 4 weeks as a 0.1%
solution in the
drinking water. Increased liver weight, centrilobular hepatocellular
hypertrophy due to increased smooth endoplasmic reticulum, decreased numbers and areas of
connexin 32-positive spots per hepatocyte, and increased cell proliferation were observed in rats treated with 0.2 and 2%
piperonyl butoxide. Similar results were obtained for 0.1%
phenobarbital treated rats. Hepatocellular
necrosis suggestive of hepatotoxicity was also observed in the 2%
piperonyl butoxide group. These results indicate that the promoting mechanism of
piperonyl butoxide in hepatocarcinogenesis is similar to that of
phenobarbital, involving an ability to induce CYP
isoenzymes and inhibit gap junctional intercellular communication. In addition, increased cell proliferation following hepatocellular
necrosis may also play a role at high doses.