Mechanistic study on liver tumor promoting effects of piperonyl butoxide in rats

Piperonyl butoxide, alpha-[2-(2-butoxy-ethoxy)ethoxy]-4,5-methylenedioxy-2- propyltoluene, 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 administ ered 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 cont rol, phenobarbital was administered to rats for up to 4 weeks as a 0.1% sol ution in the drinking water. Increased liver weight, centrilobular hepatoce llular hypertrophy due to increased smooth endoplasmic reticulum, decreased numbers and areas of connexin 32-positive spots per hepatocyte, and increa sed cell proliferation were observed in rats treated with 0.2 and 2% pipero nyl butoxide. Similar results were obtained for 0.1% phenobarbital treated rats. Hepatocellular necrosis suggestive of hepatotoxicity was also observe d in the 2% piperonyl butoxide group. These results indicate that the promo ting mechanism of piperonyl butoxide in hepatocarcinogenesis is similar to that of phenobarbital, involving an ability to induce CYP isoenzymes and in hibit gap junctional intercellular communication. In addition, increased ce ll proliferation following hepatocellular necrosis may also play a role at high doses.