Comparison of the Induction Profile of Hepatic Drug-metabolizing Enzymes Between Piperonyl Butoxide and Phenobarbital in Rats

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Male F344 rats were administered piperonyl butoxide (α[2-(2-butoxyethoxy)ethoxy]-4,5-methylenedioxy-2-propyltoluene), mixed in their diet for up to 4 weeks, and phenobarbital was administered to rats for the same period in drinking water as a positive control. We examined the changes in relative liver weight, cytochrome P450 contents, and various drugmetabolizing enzyme activities i.e., 7-alkoxycoumarin O-dealkylase activities, glutathione S-transferase activities to 1,2-dichloro-4-nitrobenzene or 1-chloro-2,4-dinitrobenzene as a substrate, and UDP-glucuronosyltransferase activity to p-nitrophenol as a substrate in the livers of those animals. All parameters examined were significantly elevated by treatment of 2% or both 0.2 and 2% piperonyl butoxide. As for P450 isozymes, induction of CYP1A1, 2B1/2, 3A, and 4A was revealed by both immunoblot analysis and immunohistochemistry. Immunohistochemistry also demonstrated that these isozymes were induced in the central zone of the hepatic lobule. These results, except for CYP1A1 induction, observed in the piperonyl butoxide-treated rats were exceedingly similar to those in the phenobarbital-treated rats used as a positive control in the present study. Phenobarbital is well-known as a promoter of liver tumor development, and consequently it has been postulated that there is a strong relationship between the promoter activity and the induction of CYP2B1/2. The present results suggest that piperonyl butoxide may act as a promoter in liver tumor development, as has recently been reported in a rat study.
日本毒性病理学会の論文
1998-03-01

Comparison of the Induction Profile of Hepatic Drug-metabolizing Enzymes Between Piperonyl Butoxide and Phenobarbital in Rats

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