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TOXICOLOGY

A Mouse Model with Liver-Specific Deletion and Global Suppression of the NADPH-Cytochrome P450 Reductase Gene: Characterization and Utility for in Vivo Studies of Cyclophosphamide Disposition

Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (J.G., Y.W., C.F., F.X., K.K., W.Y., X.D.); and Department of Biology, Boston University, Boston, Massachusetts (C.-S.C., D.J.W.)

A mouse model combining liver-specific deletion with global suppression of the NADPH-cytochrome P450 reductase gene (Cpr) has been developed and characterized. These mice (designated "Cpr-low and liver-Cpr-null" or CL-LCN) retain the respective phenotypes of the previously reported Cpr-low (CL) and liver-Cpr-null (LCN) mouse strains, but hepatic deletion of the Cpr gene occurs at an earlier age in the CL-LCN mouse than in the LCN mouse. Residual hepatic microsomal CPR activities are very low in both CL-LCN and LCN mice (at 1.5 and 2.5% of wild-type levels, respectively). The utility of CL-LCN mice for in vivo drug metabolism studies was explored using the cytochrome P450 (P450) prodrug cyclophosphamide (CPA). After i.p. injection of CPA at 100 mg/kg, the t_1/2 and the area under the concentration-time curve for plasma CPA were significantly increased in mice deficient in liver CPR compared with wild-type controls, indicating a lower rate of metabolism, with the effects greater in CL-LCN mice than in LCN mice. Correspondingly, substantial decreases in C_max, and increases in T_max, and t_1/2, of 4-hydroxycyclophosphamide (4-OH-CPA) formation were observed in both LCN and CL-LCN mice relative to wild-type controls. In contrast, CPA and 4-OH-CPA pharmacokinetic parameters were essentially unchanged in CL mice, relative to wild-type controls. The slower elimination of CPA in CL-LCN mice compared with LCN mice suggests a role for extrahepatic P450 in the in vivo metabolism of CPA and demonstrates the utility of the CL-LCN model in determining the role of extrahepatic P450 enzymes in drug metabolism and chemical toxicity.

Address correspondence to: Dr. Xinxin Ding, Wadsworth Center, New York State Department of Health, Empire State Plaza, Box 509, Albany, NY 12201-0509. E-mail: xding{at}wadsworth.org

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