Phenobarbital induction of cytochrome p-450 b,e genes is dependent on protein synthesis

Authors

  • Jose Chianale,

    1. Department of Medicine, Section of Gastroenterology, Veterans Administration Medical Center and the University of Michigan School of Medicine, Ann Arbor, Michigan 48105
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  • Leyna Mulholland,

    1. Department of Medicine, Section of Gastroenterology, Veterans Administration Medical Center and the University of Michigan School of Medicine, Ann Arbor, Michigan 48105
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  • Peter G. Traber,

    1. Department of Medicine, Section of Gastroenterology, Veterans Administration Medical Center and the University of Michigan School of Medicine, Ann Arbor, Michigan 48105
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  • Jorge J. Gumucio M.D.

    Corresponding author
    1. Department of Medicine, Section of Gastroenterology, Veterans Administration Medical Center and the University of Michigan School of Medicine, Ann Arbor, Michigan 48105
    • Department of Medicine (111D), Veterans Administration Medical Center, 2215 Fuller Road, Ann Arbor, Michigan 48105
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Abstract

Phenobarbital induces liver cytochrome P-450 b,e proteins mainly by increasing the rate of transcription of these genes. The mechanism responsible for the phenobarbital increment in the rate of transcription of cytochrome P-450 b,e genes is unknown. The objective of this study was to assess whether active protein synthesis was needed for phenobarbital to induce the liver cytochrome P-450 b,e genes. Cycloheximide (2 mg per kg, i.p.) was administered 90 min prior to a single inductive dose of phenobarbital (80 mg per kg, i.p.) and mRNAS measured at 3, 6 and 12 hr by dot-blot hybridization. While phenobarbital increased cytochrome P-450 b,e mRNAs about 12-fold at 3 hr, this induction was abolished by cycloheximide. To define whether the absence of protein synthesis in hepatocytes inhibited the phenobarbital induction of cytochrome P-450 at the transcriptional level, in vitro transcription rates using isolated nuclei were measured. After phenobarbital administration, there was about a 20-fold increment in transcriptional rate of cytochrome P-450 b,e genes. This increment was abolished by prior injection of cycloheximide. It is proposed that either preexisting regulatory proteins or transacting factors dependent on active protein synthesis participate in the regulation of liver cytochrome P-450 b,e gene transcription after phenobarbital.

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