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

Abstract

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.

Detection of non-genotoxic hepatocarcinogens and prediction of their mechanism of action in rats using gene marker sets

“…In addition, they were plotted in the enzyme inducer area in accordance with their MOA and histopathological characteristics, such as hepatocellular hypertrophy, as shown in a rodent study (data not shown). MOAs of hepatocarcinogenicity in PBO are similar to those noted with PB, such as inducing CYP2B and CYP3A and inhibiting gap junction formation (Okamiya et al, 1998). To our knowledge, the MOAs of DAM in rodent hepatocarcinogenicity …”

“…Eighteen compounds had reported hepatocarcinogenicity in rats, of which 13 (AAA, CCL4, CFB, CMA, EE, ETN, GFZ, HCB, MCT, MP, PB, TAA, and WY) were negative for mutagenicity based on information from GENETOX or other manuscripts (Gonzalez et al, 1998;Kirkland et al, 2005;Müller-Tegethoff et al, 1995;Ohta, 1993;Schiestl and Reddy, 1990) and were defined as NGTX hepatocarcinogens in this study (Table 1). In addition, given that DAM and PBO were reported as NGTX hepatocarcinogens when used in external data sets (Okamiya et al, 1998;Xie et al, 2012), these compounds were defined as NGTX hepatocarcinogens in the present study ( (Kirkland et al, 2005;Wozniak et al, 2007) and were defined as GTX hepatocarcinogens. Forty-two compounds had no hepatocarcinogenicity and were defined as non-hepatocarcinogens (Table 2).…”

The Safety Assessment of Piperonyl Butoxide

“…Further evidence of the similarity between the action of PBO and NaPB comes from a report by Okamiya et al (1998) showing an increase in proliferating cell nuclear antigen in rats fed 0.2% PBO in the diet for 4 weeks. They also demonstrated a decrease in the gap junction protein connexin 32 (Cx32) at the highest dose tested (2.0%) after dosing for 1, 2, but not 4 weeks.…”

Estrogen and androgen receptor status in hepatocellular hypertrophy induced by phenobarbital, clofibrate, and piperonyl butoxide in F344 rats

“…PBO, a pesticide synergist, was not considered as a carcinogen in humans until a strong positive result was reported in a 2-year study of F344 rats (Takahashi et al, 1994). It was suggested that the carcinogenic mechanisms of PBO are similar to those of PB in terms of induction of CYP2B and inhibition of gap junctional intercellular communication (Okamiya et al, 1998). However, the present study showed that the ER-expression and estrogen-signaling profiles of PBO were similar to those of CF but differed from those of PB.…”