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J. Biol. Chem., Vol. 283, Issue 25, 17147-17157, June 20, 2008

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Development of Oxidative Stress by Cytochrome P450 Induction in Rodents Is Selective for Barbiturates and Related to Loss of Pyridine Nucleotide-dependent Protective Systems^*

Miroslav Dostalek, Klarissa D. Hardy^¶, Ginger L. Milne^¶, Jason D. Morrow^¶, Chi Chen^||, Frank J. Gonzalez^||, Jun Gu^**, Xinxin Ding^**, Delinda A. Johnson, Jeffrey A. Johnson, Martha V. Martin, and F. Peter Guengerich¹

From the Department of Biochemistry, ^¶Division of Clinical Pharmacology, and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232-0146, the ^||Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland, 20892, the ^**Wadsworth Center, New York State Department of Health and School of Public Health, State University of New York, Albany, New York 12201-0509, and the School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705-2272

Reactive oxygen species (ROS) and oxidative stress have been considered in a variety of disease models, and cytochrome P450 (P450) enzymes have been suggested to be a source of ROS. Induction of P450s by phenobarbital (PB), β-naphthoflavone (βNF), or clofibrate in a mouse model increased ROS parameters in the isolated liver microsomes, but isoniazid treatment did not. However, when F₂-isoprostanes (F₂-IsoPs) were measured in tissues and urine, PB showed the strongest effect and βNF had a measurable but weaker effect. The same trend was seen when an Nfr2-based transgene reporter sensitive to ROS was analyzed in the mice. This pattern had been seen earlier with F₂-IsoPs both in vitro and in vivo with rats (Dostalek, M., Brooks, J. D., Hardy, K. D., Milne, G. L., Moore, M. M., Sharma, S., Morrow, J. D., and Guengerich, F. P. (2007) Mol. Pharmacol. 72, 1419–1424). One possibility for the general in vitro-in vivo discrepancy in oxidative stress found in both mice and rats is that PB treatment might attenuate protective systems. One potential candidate suggested by an mRNA microarray was nicotinamide N-methyltransferase. PB was found to elevate nicotinamide N-methyltransferase activity 3- to 4-fold in mice and rats and to attenuate levels of NAD⁺, NADP⁺, NADH, and NADPH in both species (20–40%), due to the enhanced excretion of (N-methyl)nicotinamide. PB also down-regulated glutathione peroxidase and glutathione reductase, which together constitute a key enzymatic system that uses NADPH in protecting against oxidative stress. These multiple effects on the protective systems are proposed to be more important than P450 induction in oxidative stress and emphasize the importance of studying in vivo models.

Received for publication, March 28, 2008 , and in revised form, April 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R37 CA090426 (to F. P. G.), P30 ES000267 (to F. P. G., J. D. M., and R. F. B.), P50 GM15431, R01 DK48831, and P01 ES13125 (to J. D. M.), R01 ES07462 (to X. D.), and R01 ES10042 and R01 ES08089 (to J. A. J.) from the United States Public Health Services. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Bldg., 2200 Pierce Ave., Nashville, TN 37232-0146. Tel.: 615-322-2261; Fax: 615-322-3141; E-mail: f.guengerich{at}vanderbilt.edu.

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