TY - JOUR T1 - Nrf2 Antioxidative System is Involved in Cytochrome P450 Gene Expression and Activity: A Delay in Pentobarbital Metabolism in Nrf2-deficient Mice JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.120.000010 SP - DMD-AR-2020-000010 AU - Takashi Ashino AU - Masayuki Yamamoto AU - Satoshi Numazawa Y1 - 2020/01/01 UR - http://dmd.aspetjournals.org/content/early/2020/06/05/dmd.120.000010.abstract N2 - NF-E2-related factor 2 (Nrf2) is a transcriptional regulator of biological defense proteins, such as antioxidant proteins and phase II detoxification enzymes. Cytochrome P450 (P450) enzymes have been shown to regulate phase I metabolism of various drugs and are partially regulated by Nrf2; however, the influence of Nrf2 on drug pharmacokinetics is not known. Here, we showed that Nrf2 depletion prolonged the effect of pentobarbital, a sleep-promoting drug. Pretreatment with phenobarbital, a P450 inducer, shortens the sleeping time associated with pentobarbital-induced sedation in wild-type (WT) mice; however, this effect was not observed in Nrf2−/− mice. Further, the blood pentobarbital concentration was higher in Nrf2−/− mice than in WT mice at 30-60 min, and the phenobarbital-induced enhancement of its clearance was attenuated in Nrf2−/− mice compared to WT mice. Total P450 content was decreased in Nrf2−/− mouse livers, and the phenobarbital-induced increase in P450 content was lower in Nrf2−/− mice than WT mice. Cyp1a2, Cyp2a5, Cyp2c29, and Cyp2e1 gene expression levels under physiological conditions and Cyp1a2, Cyp2a5, and Cyp2b10 gene expression levels under phenobarbital-treated conditions were lower in Nrf2−/− mice compared to WT mice. Additionally, pentobarbital metabolism in liver microsomes was attenuated by Nrf2 depletion. Taken together, these findings suggested that Nrf2 influenced pentobarbital pharmacokinetics through the regulation of drug metabolism and P450 gene expression. Thus, Nrf2-mediated regulation of P450 may contribute to the biological defense against increased reactive oxygen species production. ER -