We studied the impact of administering XPro1595, a novel antagonist of soluble tumor necrosis factor-α (TNFα), on the regulation of hepatic cytochrome P450 enzymes in the C. rodentium model of infectious colitis. XPro1595 was administered subcutaneously every three days throughout the infection, or as a single injection near the peak of infection. When given throughout the infection, XPro1595 selectively blocked the down-regulation of Cyp3a11 and 3a25 mRNAs, as well as the induction of Cyp2a4/5, without affecting the down-regulation 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 a) confirm the role of soluble TNFα in hepatic Cyp3a regulation during infectious colitis deduced from studies in TNFα receptor-1 knockout mice; b) indicate the potential for soluble TNFα-specific antagonists to cause disease-dependent drug-drug interactions; and, c) suggest a novel mechanism by which an anti-inflammatory therapeutic protein can produce an opposite effect to that of the disease by selectively neutralizing one of multiple signals regulating drug-metabolizing enzyme expression. More research is needed to determine whether or not this is applicable to other diseases or disease models.
by
Shashi Bhushan;
Kazuhisa Kondo;
David Polhemus;
Hiroyuki Otsuka;
Chad Nicholson;
Ya-Xiong Tao;
Hui Huang;
Vasiliki Georgiopoulou;
Toyoaki Murohara;
John Calvert;
Javed Butler;
David J. Lefer