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Rapid CommunicationShort Communication

Rat Cytochrome P450 1A and 3A Enzymes Involved in Bioactivation of Tegafur to 5-Fluorouracil and Autoinduced by Tegafur in Liver Microsomes

Hiroshi Yamazaki, Tomoko Komatsu, Kei Takemoto, Noriaki Shimada, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition June 2001, 29 (6) 794-797;
Hiroshi Yamazaki
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Tomoko Komatsu
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Kei Takemoto
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Noriaki Shimada
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Miki Nakajima
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Tsuyoshi Yokoi
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Abstract

Tegafur, an anticancer prodrug, is reported to be bioactivated to 5-fluorouracil (5-FU) by cytochrome P450 (P450) enzymes. Liver microsomal P450 enzymes involved in the biotransformation of tegafur into 5-FU in rats and the effect of tegafur in vivo on P450 levels in rats were investigated. Of 12 cDNA-expressed rat P450 enzymes tested, CYP1A2, CYP3A1, and CYP2C11 had high 5-FU formation rates from 100 μM and 1.0 mM tegafur concentrations. The contributions of CYP1A, CYP2C, and CYP3A enzymes to 5-FU formation in male rat liver microsomes were supported by immunoinhibition studies. 5-FU formation from tegafur, at substrate concentrations of 100 μM and 1.0 mM, was increased by intraperitoneal treatment of tegafur (50 mg/kg for 5 days) as well as by β-naphthoflavone, phenobarbital, and dexamethasone. Orally administered tegafur (100 mg/kg daily for 20 days) caused the induction of CYP2B (5-fold) and of CYP1A and CYP3A (∼2-fold) and of 5-FU formation (∼2-fold) in rat liver microsomes. These results suggest that CYP1A and CYP3A enzymes, autoinduced by tegafur, have important roles in 5-FU formation from tegafur in rat liver microsomes. Coadministration of tegafur and P450-inducing drugs could markedly enhance the biotransformation of tegafur into 5-FU via P450 induction.

Footnotes

  • Send reprint requests to: Hiroshi Yamazaki, Ph.D., Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan. E-mail: yamazak{at}kenroku.kanazawa-u.ac.jp

  • Supported in part by a grant-in-aid from the Ministry of Education, Science, Sports, and Culture of Japan, the Ministry of Health and Welfare of Japan, and Takeda Science Foundation.

  • Abbreviations used are::
    5-FU
    5-fluorouracil
    P450
    general term for cytochrome P450
    NPR
    NADPH-cytochrome P450 reductase
    • Received October 12, 2000.
    • Accepted March 4, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (6)
Drug Metabolism and Disposition
Vol. 29, Issue 6
1 Jun 2001
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Rapid CommunicationShort Communication

Rat Cytochrome P450 1A and 3A Enzymes Involved in Bioactivation of Tegafur to 5-Fluorouracil and Autoinduced by Tegafur in Liver Microsomes

Hiroshi Yamazaki, Tomoko Komatsu, Kei Takemoto, Noriaki Shimada, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition June 1, 2001, 29 (6) 794-797;

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Rapid CommunicationShort Communication

Rat Cytochrome P450 1A and 3A Enzymes Involved in Bioactivation of Tegafur to 5-Fluorouracil and Autoinduced by Tegafur in Liver Microsomes

Hiroshi Yamazaki, Tomoko Komatsu, Kei Takemoto, Noriaki Shimada, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition June 1, 2001, 29 (6) 794-797;
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