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DIFFERENTIAL REGULATION OF THE HUMAN CYP3A4 PROMOTER IN TRANSGENIC MICE AND RATS

Weisheng Zhang, Anthony F. Purchio, Richard Coffee and David B. West
Drug Metabolism and Disposition February 2004, 32 (2) 163-167; DOI: https://doi.org/10.1124/dmd.32.2.163
Weisheng Zhang
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Anthony F. Purchio
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Richard Coffee
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David B. West
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Abstract

Previously we described a transgenic mouse model [FVB/NTg(CYP3A4-luc)Xen] using a reporter construct consisting of 13 kilobases of the human CYP3A4 promoter driving the firefly luciferase gene in the inbred FVB/N mouse strain. Here we report regulation of the same CYP3A4-luc reporter gene in a transgenic outbred mouse strain (CD-1) and in a transgenic rat (Sprague-Dawley). Basal reporter expression and responses to several xenobiotics in the transgenic CD-1 mice [CD-1/Crl-Tg(CYP3A4-luc)Xen] were similar to those in the transgenic FVB/N mice. In both mouse backgrounds, the basal levels of the reporter were higher in male compared with female, and in the FVB/N strain there was greater induction for all drugs in male compared with female; however, in the CD-1 background this gender difference for induction was not obvious. In contrast with transgenic mice, transgenic rats [SD/Tac-Tg(CYP3A4-luc)Xen] expressed the luciferase reporter at higher basal levels in female compared with male rats. Responses to some compounds were much greater in rats than in mice, and the kinetics of induction was different with peak induction occurring later in the rat compared with the mouse. Our results suggest that the human CYP3A4 promoter is regulated differently in transgenic mice and rats in some aspects.

Footnotes

  • ↵1 Abbreviations used are: P450, cytochrome P450; PXR, pregnane X receptor; SD, Sprague-Dawley; PCN, 5-pregnen-3β-ol-20-one-16α-carbonitrile; DMSO, dimethyl sulfoxide; kb, kilobase.

    • Received May 30, 2003.
    • Accepted September 25, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (2)
Drug Metabolism and Disposition
Vol. 32, Issue 2
1 Feb 2004
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OtherShort Communication

DIFFERENTIAL REGULATION OF THE HUMAN CYP3A4 PROMOTER IN TRANSGENIC MICE AND RATS

Weisheng Zhang, Anthony F. Purchio, Richard Coffee and David B. West
Drug Metabolism and Disposition February 1, 2004, 32 (2) 163-167; DOI: https://doi.org/10.1124/dmd.32.2.163

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OtherShort Communication

DIFFERENTIAL REGULATION OF THE HUMAN CYP3A4 PROMOTER IN TRANSGENIC MICE AND RATS

Weisheng Zhang, Anthony F. Purchio, Richard Coffee and David B. West
Drug Metabolism and Disposition February 1, 2004, 32 (2) 163-167; DOI: https://doi.org/10.1124/dmd.32.2.163
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