Distinct effects of phenobarbital and its N-methylated derivative on liver cytochrome P450 induction

Norie Murayama, Miki Shimada, Yasushi Yamazoe, Kazuhiro Sogawa, Kazuo Nakayama, Yoshiaki Fujii-Kuriyama, Ryuichi Kato

    Research output: Contribution to journalArticle

    18 Citations (Scopus)

    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 mM barbital, 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 observed in vivo in rats treated with PB and N-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 or N-methyl-PB alone, but decreased by cotreatment with 1 mM PB and N-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.

    Original languageEnglish
    Pages (from-to)184-192
    Number of pages9
    JournalArchives of Biochemistry and Biophysics
    Volume328
    Issue number1
    DOIs
    Publication statusPublished - 1996 Apr 1

    Keywords

    • CYP2B
    • CYP3A
    • barbiturates
    • cytochrome P450
    • hepatocytes
    • induction

    ASJC Scopus subject areas

    • Biophysics
    • Biochemistry
    • Molecular Biology

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  • Cite this

    Murayama, N., Shimada, M., Yamazoe, Y., Sogawa, K., Nakayama, K., Fujii-Kuriyama, Y., & Kato, R. (1996). Distinct effects of phenobarbital and its N-methylated derivative on liver cytochrome P450 induction. Archives of Biochemistry and Biophysics, 328(1), 184-192. https://doi.org/10.1006/abbi.1996.0159