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Accelerated Communication

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

Department of Biochemistry (M.D., F.P.G.), Division of Clinical Pharmacology (J.D.B., K.D.H., G.L.M., M.M.M., S.S., J.D.M.), and Center in Molecular Toxicology (G.L.M., J.D.M., F.P.G.), Vanderbilt University School of Medicine, Nashville, Tennessee

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 (-naphthoflavone, phenobarbital (PB), Aroclor 1254, isoniazid, pregnenolone 16-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.

Address correspondence to: Prof. F. Peter Guengerich, Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Bldg, 2200 Pierce Ave, Nashville, TN 37232-0146. E-mail: f.guengerich{at}vanderbilt.edu

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