Considerations for Use of Recombinant Adenoviral Vectors: Dose Effect on Hepatic Cytochromes P450

• Published in: The Journal of pharmacology and experimental therapeutics 2005-02, Vol.312 (2), p.492-501
• Main Authors: Callahan, Shellie M, Ming, Xin, Lu, Shirley K, Brunner, Lane J, Croyle, Maria A
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Alanine Transaminase - blood; Animals; Aspartate Aminotransferases - blood; beta-Galactosidase - biosynthesis; beta-Galactosidase - genetics; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Escherichia coli - drug effects; Escherichia coli - enzymology; Genetic Vectors - genetics; Isoenzymes - biosynthesis; Isoenzymes - genetics; Lac Operon - genetics; Liver - enzymology; Liver Function Tests; Male; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Rats; Rats, Sprague-Dawley; Recombination, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - isolation & purification; Transgenes - genetics; Viral Plaque Assay
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.104.075374

Recombinant adenovirus (Ad) serotype 5 is a vector commonly used for gene delivery. Although this vector has a natural tropism for the liver, there is a limited understanding of how Ad administration affects one of the primary hepatic processes, drug metabolism. The effects of systemic administration of a model recombinant adenoviral vector on two hepatic cytochrome P450 (P450) enzymes, CYP3A2 and 2C11, were investigated. Sprague-Dawley rats were treated with one of six vector doses, ranging from 5.7 × 10 6 to 5.7 × 10 12 virus particles (vp)/kg. Hepatic P450 protein expression, catalytic activity, and mRNA levels were measured over 14 days. Ad administration (5.7 × 10 10 -5.7 × 10 12 vp/kg) reduced CYP3A2 over the duration of the study. Six hours after administration of 5.7 × 10 12 vp/kg, CYP3A2 activity and mRNA levels were suppressed by 45 and 65%, respectively ( P ≤ 0.01). This continued throughout the study with levels dropping to 36 and 45% of controls by 14 days, respectively ( P ≤ 0.01). A similar trend was detected for CYP2C11 within this dosing range. Administration of 5.7 × 10 6 , 5.7 × 10 8 , and 5.7 × 10 9 vp/kg of Ad significantly increased both CYP2C11 protein expression by 86, 71, and 107% and activity 110, 118, and 53%, respectively, above those of animals treated with saline ( P ≤ 0.01). These results clearly indicate that a single dose of adenovirus significantly alters key drug metabolizing enzymes for an extended period of time and should be investigated further in the context of the design and implementation of clinical trial protocols.