Distinct Effects of Phenobarbital and Its N-Methylated Derivative on Liver Cytochrome P450 Induction

doi:10.1006/abbi.1996.0159

Archives of Biochemistry and Biophysics

Volume 328, Issue 1, 1 April 1996, Pages 184-192

https://doi.org/10.1006/abbi.1996.0159 Get rights and content

Abstract

The relationship between barbiturate structures and their effects on induction of rat cytochrome P450 forms was studied in primary cultured hepatocytes. Treatment of hepatocytes cultured on matrigel with 1 mMbarbital,N-methylbarbital, cyclobarbital, hexobarbital, phenobarbital (PB), or mephobarbital (N-methyl-PB) resulted in increased amounts of CYP2B1/2 and CYP2C6 forms. Microsomal CYP3A content was also enhanced by treatment with these barbiturates, except for barbital. Although no relationship was observed between the levels of CYP2B1/2 and CYP3A, ratios of CYP3A/CYP2B1 plus CYP2B2 contents were invariably higher with hepatocytes treated with N-methylated barbiturates than with the nonmethylated analogs. Consistent results were also observedin vivoin rats treated with PB andN-methyl-PB. These results indicate the difference in the structure requirement for induction of CYP2B and CYP3A. In addition,N-methyl-PB was found to suppress PB-mediated induction of CYP2B1. Hepatic levels of CYP2B1 mRNA and protein were increased by treatment with PB orN-methyl-PB alone, but decreased by cotreatment with 1 mMPB andN-methyl-PB. The suppression has been shown to occur at the transcriptional level of the CYP2B1 gene by using a chloramphenicol acetyltransferase reporter–CYP2B1 fused gene system.

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Citation Excerpt :
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Regular ArticleDistinct Effects of Phenobarbital and Its N-Methylated Derivative on Liver Cytochrome P450 Induction

Abstract

Regular Article
Distinct Effects of Phenobarbital and Its N-Methylated Derivative on Liver Cytochrome P450 Induction