Renal pathophysiology after systemic administration of recombinant adenovirus: changes in renal cytochromes P450 based on vector dose.
Recombinant adenovirus (Ad) significantly alters hepatic cytochrome P450 (CYP). Because changes in renal function can alter hepatic CYP, the effect of Ad on renal CYPs 4A1, 4A2, 4F1, and 2E1 was evaluated. Male Sprague-Dawley rats were given one of six intravenous doses (5.7x10(6)-5.7x10(12) viral particles/kg [VP/kg]) of Ad expressing beta-galactosidase or saline. CYP protein, activity, gene expression, and serum creatinine (SCr) were evaluated 0.25, 1, 4, and 14 days later. Doses of 5.7x10(11) and 5.7x10(12) VP/kg increased CYP4A protein within 24 hr by 35 and 48%, respectively (p<0.05). A similar trend was observed on day 4. CYP4A1 mRNA doubled 6 hr after doses of 5.7x10(10)-10(12) VP/kg (p<0.01). Similar effects were observed 1 day after each dose tested. CYP4A2 gene expression was 20% above control 1 day after treatment with 5.7x10(10)-10(12) VP/kg and remained high through day 14. CYP4F1 expression was unaffected by all doses (p=0.08). CYP2E1 activity and gene expression were significantly suppressed 24 hr after administration of all doses and began to normalize by day 14 (p<0.01). SCr was significantly reduced (approximately 50%) throughout the study for doses at and below 5.7x10(11) VP/kg. SCr was increased by a factor of 3 by 5.7x10(12) VP/kg and glomerular filtration was significantly reduced (p<0.01). This suggests that changes in renal CYP and corresponding arachidonic acid metabolites may play a role in the documented toxicity associated with the systemic administration of recombinant Ad.
Le
Hong T
HT
Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA.
Boquet
Michael P
MP
Clark
Erin A
EA
Callahan
Shellie M
SM
Croyle
Maria A
MA
D000256:Adenoviridae; D000818:Animals; D003404:Creatinine / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005822:Genetic Vectors / Q000008:administration & dosage / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology
D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D003404:Creatinine