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Research ArticleArticle

Dose of Phenobarbital and Age of Treatment at Early Life are Two Key Factors for the Persistent Induction of Cytochrome P450 Enzymes in Adult Mouse Liver

Yun-Chen Tien, Ke Liu, Chad Pope, Pengcheng Wang, Xiaochao Ma and Xiao-bo Zhong
Drug Metabolism and Disposition December 2015, 43 (12) 1938-1945; DOI: https://doi.org/10.1124/dmd.115.066316
Yun-Chen Tien
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (Y.C.T., C.P., X.B.Z.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (K.L., P.W., X.M.)
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Ke Liu
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (Y.C.T., C.P., X.B.Z.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (K.L., P.W., X.M.)
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Chad Pope
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (Y.C.T., C.P., X.B.Z.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (K.L., P.W., X.M.)
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Pengcheng Wang
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (Y.C.T., C.P., X.B.Z.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (K.L., P.W., X.M.)
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Xiaochao Ma
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (Y.C.T., C.P., X.B.Z.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (K.L., P.W., X.M.)
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Xiao-bo Zhong
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (Y.C.T., C.P., X.B.Z.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (K.L., P.W., X.M.)
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Abstract

Drug treatment of neonates and infants and its long-term consequences on drug responses have emerged in recent years as a major challenge for health care professionals. In the current study, we use phenobarbital as a model drug and mouse as an in vivo model to demonstrate that the dose of phenobarbital and age of treatment are two key factors for the persistent induction of gene expression and consequential increases of enzyme activities of Cyp2b, Cyp2c, and Cyp3a in adult livers. We show that phenobarbital treatment at early life of day 5 after birth with a low dose (<100 mg/kg) does not change expression and enzyme activities of Cyp2b, Cyp2c, and Cyp3a in adult mouse liver, whereas phenobarbital treatment with a high dose (>200 mg/kg) significantly increases expression and enzyme activities of these P450s in adult liver. We also demonstrate that phenobarbital treatment before day 10 after birth, but not at later ages, significantly increases mRNAs, proteins, and enzyme activities of the tested P450s. Such persistent induction of P450 gene expression and enzyme activities in adult livers by phenobarbital treatment only occurs within a sensitive age window early in life. The persistent induction in gene expression and enzyme activities is higher in female mice than in male mice for Cyp2b10 but not for Cyp2c29 and Cyp3a11. These results will stimulate studies to evaluate the long-term impacts of drug treatment with different doses at neonatal and infant ages on drug metabolism, therapeutic efficacy, and drug-induced toxicity throughout the rest of life.

Footnotes

    • Received July 16, 2015.
    • Accepted September 21, 2015.
  • This study was supported by the National Institutes of Health National Institute for Environmental Health Science [Grant R01ES-019487] (to X.B.Z), National Institute of General Medical Sciences [Grant R01GM-087376] (to X.B.Z), and National Institute for Diabetes and Digestive and Kidney Diseases [Grant R01DK090305] (to X.M).

  • dx.doi.org/10.1124/dmd.115.066316.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (12)
Drug Metabolism and Disposition
Vol. 43, Issue 12
1 Dec 2015
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Research ArticleArticle

Persistent Induction of P450s by Phenobarbital Treatment

Yun-Chen Tien, Ke Liu, Chad Pope, Pengcheng Wang, Xiaochao Ma and Xiao-bo Zhong
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1938-1945; DOI: https://doi.org/10.1124/dmd.115.066316

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Research ArticleArticle

Persistent Induction of P450s by Phenobarbital Treatment

Yun-Chen Tien, Ke Liu, Chad Pope, Pengcheng Wang, Xiaochao Ma and Xiao-bo Zhong
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1938-1945; DOI: https://doi.org/10.1124/dmd.115.066316
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