Open AccessSelective effects of a therapeutic protein targeting tumor necrosis factor‐alpha on cytochrome P450 regulation during infectious colitis: implications for disease‐dependent drug–drug interactions
Author(s) -
Nyagode Beatrice A.,
Jahangardi Roya,
Merrell Matthew D.,
Tansey Malú G.,
Morgan Edward T.
Publication year - 2014
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.27
Subject(s) - tumor necrosis factor alpha , downregulation and upregulation , drug , colitis , cytochrome p450 , pharmacology , disease , medicine , immunology , gene knockdown , cancer research , biology , gene , biochemistry , metabolism
Abstract We studied the impact of administering XPro1595, a novel antagonist of soluble tumor necrosis factor‐ α (TNF α ), on the regulation of hepatic cytochrome P450 enzymes in the Citrobacter rodentium model of infectious colitis. XPro1595 was administered subcutaneously every 3 days throughout the infection, or as a single injection near the peak of infection. When given throughout the infection, XPro1595 selectively blocked the downregulation of Cyp3a11 and 3a25 mRNAs, as well as the induction of Cyp2a4/5, without affecting 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 role of soluble TNF α in hepatic Cyp3a regulation during infectious colitis deduced from studies in TNF α receptor‐1 knockout mice; (2) indicate the potential for soluble TNF α ‐specific antagonists to cause disease‐dependent drug–drug interactions; and (3) 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.