Molecular and macromolecular alterations of recombinant adenoviral vectors do not resolve changes in hepatic drug metabolism during infection.
In this report we test the hypothesis that long-term virus-induced alterations in CYP occur from changes initiated by the virus that may not be related to the immune response. Enzyme activity, protein expression and mRNA of CYP3A2, a correlate of human CYP3A4, and CYP2C11, responsive to inflammatory mediators, were assessed 0.25, 1, 4, and 14 days after administration of several different recombinant adenoviruses at a dose of 5.7 x 1012 virus particles (vp)/kg to male Sprague Dawley rats. Wild type adenovirus, containing all viral genes, suppressed CYP3A2 and 2C11 activity by 37% and 39%, respectively within six hours. Levels fell to 67% (CYP3A2) and 79% (CYP2C11) of control by 14 days (p <or= 0.01). Helper-dependent adenovirus, with all viral genes removed, suppressed CYP3A2 (43%) and CYP2C11 (55%) within six hours. CYP3A2 remained significantly suppressed (47%, 14 days, p <or= 0.01) while CYP2C11 returned to baseline at this time. CYP3A2 and 2C11 were reduced by 45 and 42% respectively 6 hours after treatment with PEGylated adenovirus, which has a low immunological profile (p <or= 0.05). CYP3A2 remained suppressed (34%, p <or= 0.05) for 14 days while CYP2C11 recovered. Inactivated virus suppressed CYP3A2 activity by 25-50% for 14 days (p <or= 0.05). CYP2C11 was affected similar manner but recovered by day 14. Microarray and in vitro studies suggest that changes in cellular signaling pathways initiated early in virus infection contribute to changes in CYP.
Callahan
Shellie M
SM
College of Pharmacy, Division of Pharmaceutics, The University of Texas at Austin, Austin, TX, USA. smcallahan@gmail.com
Wonganan
Piyanuch
P
Croyle
Maria A
MA
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000257:Adenoviridae Infections / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology / Q000821:virology; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000821:virology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*
D008565:Membrane Proteins; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D000410:Alanine Transaminase