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OtherTOXICOLOGY

UDP-Glucuronosyltransferase-mediated Protection Against In Vitro DNA Oxidation and Micronucleus Formation Initiated by Phenytoin and Its Embryotoxic Metabolite 5-(p-Hydroxyphenyl)-5-phenylhydantoin

Perry M. Kim, Louise M. Winn, Toufan Parman and Peter G. Wells
Journal of Pharmacology and Experimental Therapeutics January 1997, 280 (1) 200-209;
Perry M. Kim
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Louise M. Winn
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Toufan Parman
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Peter G. Wells
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Abstract

UDP-Glucuronosyltransferases (UGTs) are important in the elimination of most xenobiotics, including 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), the major, reputedly nontoxic, metabolite of the anticonvulsant drug phenytoin. However, HPPH alternatively may be bioactivated by peroxidases, such as prostaglandin H synthase, to a reactive intermediate that initiates DNA oxidation (reflected by 8-hydroxy-2′-deoxyguanosine), genotoxicity (reflected by micronuclei) and embryopathy. This hypothesis was evaluated in skin fibroblasts cultured from heterozygous (+/j) and homozygous (j/j) UGT-deficient Gunn rats and in mouse embryo culture, with confirmation of directN 3-glucuronidation of phenytoin in Gunn ratsin vivo. HPPH (80 μM) increased micronuclei by 2.0-, 4.8- and 4.6-fold in +/+ UGT-normal cells (P = .03) and +/jand j/j UGT-deficient cells (P = .0001), respectively. HPPH-initiated micronucleus formation was increased 3.0- and 3.4-fold in +/j (P = .02) and j/j (P = .04) UGT-deficient cells, respectively, vs. +/+ UGT-normal cells. Micronuclei were not initiated by 10 μM HPPH in +/+ UGT-normal cells but were increased by 4- and 3.8-fold in +/j andj/j UGT-deficient cells (P = .0001), respectively, and were increased 2.7- and 3.0-fold in +/j (P = .007) andj/j (P = .0002) UGT-deficient cells, respectively,vs. +/+ UGT-normal cells. 8-Hydroxy-2′-deoxyguanosine was increased in j/j UGT-deficient but not +/+ UGT-normal cells treated with 80 μM HPPH (P < .05). The embryopathic potency of 80 μM HPPH in embryo culture, reflected by decreases in anterior neuropore closure, turning, yolk sac diameter and crown-rump length (P < .05), was equivalent to that reported for phenytoin. Phenytoin (80 μM) enhanced micronucleus formation 1.7-, 4.4- and 3.8-fold in +/+ cells (P = .03) and +/j andj/j UGT-deficient cells (P = .0001), respectively. Phenytoin-initiated micronucleus formation was increased about 4-fold in both +/j (P = .006) and j/j (P = .009) UGT-deficient cells vs. +/+ UGT-normal cells, providing the first evidence that the bioactivation and oxidative toxicity of phenytoin itself may be avoided by directN-glucuronidation, which was confirmed by tandem mass spectrometry. These results further indicate that, with UGT deficiencies, HPPH potentially is a potent mediator of phenytoin-initiated genotoxicity and embryopathy, which may be relevant to teratogenesis and other adverse effects of phenytoin.

Footnotes

  • Send reprint requests to: Peter G. Wells, Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada M5S 2S2.

  • ↵1 A preliminary report of this research was presented at the 35th Annual Meeting of the Society of Toxicology (Wells and Kim, 1996). This research was supported by a grant from the Medical Research Council of Canada.

  • Abbreviations:
    B[a]P
    benzo[a]pyrene
    DMSO
    dimethylsulfoxide
    FBS
    fetal bovine serum
    HBSS
    Hanks’ balanced salt solution
    HPLC
    high-performance liquid chromatography
    HPPH
    5-(p-hydroxyphenyl)-5-phenylhydantoin
    MS
    mass spectrometry
    NNK
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
    8-OH-2′-dG
    8-hydroxy-2′-deoxyguanosine
    P450
    cytochrome P450
    PBS
    phosphate-buffered saline
    PHS
    prostaglandin H synthase
    UGT
    UDP-glucuronosyltransferase
    • Received June 10, 1996.
    • Accepted September 3, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 1
1 Jan 1997
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OtherTOXICOLOGY

UDP-Glucuronosyltransferase-mediated Protection Against In Vitro DNA Oxidation and Micronucleus Formation Initiated by Phenytoin and Its Embryotoxic Metabolite 5-(p-Hydroxyphenyl)-5-phenylhydantoin

Perry M. Kim, Louise M. Winn, Toufan Parman and Peter G. Wells
Journal of Pharmacology and Experimental Therapeutics January 1, 1997, 280 (1) 200-209;

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OtherTOXICOLOGY

UDP-Glucuronosyltransferase-mediated Protection Against In Vitro DNA Oxidation and Micronucleus Formation Initiated by Phenytoin and Its Embryotoxic Metabolite 5-(p-Hydroxyphenyl)-5-phenylhydantoin

Perry M. Kim, Louise M. Winn, Toufan Parman and Peter G. Wells
Journal of Pharmacology and Experimental Therapeutics January 1, 1997, 280 (1) 200-209;
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