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1995). the downregulation of Cyp3a11 and 3a25 mRNAs, as well as the induction of Cyp2a4/5, without influencing the downregulation of Cyp4a10, Cyp4a14, Cyp2b10, or flavin-mooxygenase-3. Induction of Cyp3a11, Cyp3a25, Cyp2c29, and Cyp3a13 mRNAs were observed only in XPro1595-treated mice. Administration of a single dose of XPro1595 was relatively ineffective. These results (1) confirm the part of soluble TNFin hepatic Cyp3a rules JNJ 1661010 during infectious colitis deduced from studies in TNFreceptor-1 knockout mice; (2) show the potential for soluble TNF-specific antagonists to cause disease-dependent drugCdrug relationships; and (3) suggest a novel mechanism by which an anti-inflammatory restorative protein can produce an opposite effect to that of the disease by selectively neutralizing one of multiple signals regulating drug-metabolizing enzyme manifestation. More study is needed to determine whether or not this is relevant to additional diseases or disease models. or are thought to mediate the effects of swelling on P450 regulation. While it has been shown that such cytokines can regulate P450 expression in hepatocyte cultures (Abdel-Razzak et al. 1993; Chen et al. 1995; Tapner et al. 1996; Aitken and Morgan 2007; Dickmann et al. 2012) and in vivo (Renton et al. 1984; Ghezzi et al. 1986a,b; Morgan et al. 1994), the functions of individual cytokines on regulation of drug metabolism in different diseases are not well understood. The need to understand which cytokines are involved in P450 regulation in vivo is usually sharpened by the recently discovered phenomenon of disease-dependent drugCdrug interactions (DDDI), in which therapeutic proteins (biologic drugs) targeted CAPZA1 toward cytokines or their receptors can affect the metabolism of small molecule drugs by reversing the downregulation of P450 enzymes caused by the inflammatory disease, as examined in (Morgan 2009). This was first demonstrated by the attenuation of Cyp3a downregulation in mice by a polyclonal antibody to IL-6 in a genetic model of arthritis (Ashino et al. 2007). Cyp3a downregulation in a different, preadjuvant model JNJ 1661010 of arthritis was inhibited by the anti-TNFbiologic infliximab (Ling and Jamali 2009). Subsequently, the anti-IL-6 receptor antibody tocilizumab was shown to increase clearance of the CYP3A substrate simvastatin in humans with rheumatoid arthritis (Schmitt et al. 2011). A recent white paper on the subject illustrates both the clinical and regulatory issues for JNJ 1661010 DDDIs and the need for more information on cytokine JNJ 1661010 regulation of P450s during inflammatory disease (Evers et al. 2013). In addition to the study using infliximab explained above, four other studies have directly tested the in vivo role of TNFin P450 regulation in a disease model. The downregulations of Cyp1a, 2b, 3a, and 4a following bacterial lipopolysaccharide (LPS) injection were not attenuated in mice deficient in both TNFreceptor-1 (TNFR1) and TNFR2, (Warren et al. 1999), whereas the responses of JNJ 1661010 Cyp2d and Cyp2e1 enzymes were attenuated. In agreement with this obtaining, Cyp3a11 and 2c29 downregulations by LPS were unaffected in TNFis an important factor in selectively regulating the expression of P450s of the Cyp3a subfamily in is usually a noninvasive rodent pathogen equivalent to human enteropathogenic that causes colitis in humans (Higgins et al. 1999). The colitis caused by the bacteria is usually characteristic of inflammatory bowel disease (Higgins et al. 1999). Cyp3a11 and Cyp3a25 were significantly downregulated in was the most potent and efficacious cytokine tested in the downregulation of Cyp3a enzymes and other P450s in mouse hepatocyte cultures (Nyagode et al. 2010; Kinloch et al. 2011). Together, these results suggest a role for TNFin the regulation of Cyp3a enzymes in vivo, which is dependent on the specific disease or disease model. However, the lack of Cyp3a downregulation observed in TNFeffects. This possibility can be resolved using a pharmacological approach to block TNFaction in wild-type mice. The biologic drugs currently in clinical use do not discriminate between soluble or membrane-bound forms of TNFto eliminate the potential influence of these adaptive changes. We used XPro1595, a dominant-negative form of TNF(Y87H, A145R) that forms heterotrimers with native soluble TNFto give complexes that neither bind to nor stimulate signaling through TNFreceptors (Steed et al. 2003; Zalevsky et al. 2007). This experiment was designed to test.