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Molecular Pharmacology

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In Vivo Oxidative Damage in Rats Is Associated with Barbiturate Response but Not Other Cytochrome P450 Inducers

Miroslav Dostalek, Joshua D. Brooks, Klarissa D. Hardy, Ginger L. Milne, Megan M. Moore, Sameer Sharma, Jason D. Morrow and F. Peter Guengerich
Molecular Pharmacology December 2007, 72 (6) 1419-1424; DOI: https://doi.org/10.1124/mol.107.040238
Miroslav Dostalek
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Joshua D. Brooks
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Klarissa D. Hardy
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Ginger L. Milne
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Megan M. Moore
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Sameer Sharma
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Jason D. Morrow
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F. Peter Guengerich
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Abstract

Previously published studies have shown that cytochrome P450 (P450) enzyme systems can produce reactive oxygen species and suggest roles of P450s in oxidative stress. However, most of the studies have been done in vitro, and the potential link between P450 induction and in vivo oxidative damage has not been rigorously explored with validated biomarkers. Male Sprague-Dawley rats were pretreated with typical P450 inducers (β-naphthoflavone, phenobarbital (PB), Aroclor 1254, isoniazid, pregnenolone 16α-carbonitrile, and clofibrate) or the general P450 inhibitor 1-aminobenztriazole; induction of P4501A, -2B, -2E, -3A, and -4A subfamily enzymes was confirmed by immunoblotting and the suppression of P450 by 1-aminobenztriazole using spectral analysis. PB and Aroclor 1254 significantly enhanced malondialdehyde and H2O2 generation and NADPH oxidation in vitro and significantly enhanced formation in vivo, in both liver and plasma. Some of the other treatments changed in vitro parameters but none did in vivo. The PB-mediated increases in liver and plasma F2-isoprostanes could be ablated by 1-aminobenztriazole, implicating the PB-induced P450(s) in the F2-isoprostane elevation. The markers of in vivo oxidative stress were influenced mainly by PB and Aroclor 1254, indicative of an oxidative damage response only to barbiturate-type induction and probably related to 2B subfamily enzymes. These studies define the contribution of P450s to oxidative stress in vivo, in that the phenomenon is relatively restricted and most P450s do not contribute substantially.

Footnotes

  • ↵1 A literature search yielded only limited studies of the effect of barbiturates on production of reactive oxygen species in cell culture [e.g., a recent study in chicken hepatocytes in which a dye assay was used (Blättler et al., 2007)].

  • ↵2 The literature indicates a t1/2 for plasma isoniazid of 0.4 h irrespective of route of administration (Belanger et al., 1989). Thus, 30 half-lives elapsed before the samples were analyzed, and the residual level of isoniazid should have been very low.

  • ↵3 An additional load on the oxidative defense systems could conceivably exacerbate an effect of P450 induction (e.g., glutathione depletion). We focused on the effect of P450 induction per se in that glutathione depletion by itself is known to raise F2-IsoP levels (Morrow et al., 1998).

  • This work was supported by U.S. Public Health Service grants R37-CA090426 (to F.P.G.), P50-GM15431 (to J.D.M.), P01-CA77839 (to J.D.M.), R01-DK48831 (to J.D.M.), P01-ES13125 (to J.D.M.), T32-ES007028 (to J.D.B., F.P.G.), and P30-ES000267 (to F.P.G., J.D.M).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.040238.

  • ABBREVIATIONS: P450, cytochrome P450; 1-ABT, 1-aminobenztriazole; F2-IsoP, F2-isoprostane; βNF, β-naphthoflavone; CLOF, clofibrate; INH, isoniazid; Aroclor, Aroclor 1254 (a commercial mixture of polychlorinated biphenyls); PCN, pregnenolone 16α-carbonitrile; PB, phenobarbital.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received July 20, 2007.
    • Accepted September 26, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (6)
Molecular Pharmacology
Vol. 72, Issue 6
1 Dec 2007
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In Vivo Oxidative Damage in Rats Is Associated with Barbiturate Response but Not Other Cytochrome P450 Inducers

Miroslav Dostalek, Joshua D. Brooks, Klarissa D. Hardy, Ginger L. Milne, Megan M. Moore, Sameer Sharma, Jason D. Morrow and F. Peter Guengerich
Molecular Pharmacology December 1, 2007, 72 (6) 1419-1424; DOI: https://doi.org/10.1124/mol.107.040238

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In Vivo Oxidative Damage in Rats Is Associated with Barbiturate Response but Not Other Cytochrome P450 Inducers

Miroslav Dostalek, Joshua D. Brooks, Klarissa D. Hardy, Ginger L. Milne, Megan M. Moore, Sameer Sharma, Jason D. Morrow and F. Peter Guengerich
Molecular Pharmacology December 1, 2007, 72 (6) 1419-1424; DOI: https://doi.org/10.1124/mol.107.040238
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