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 (5.7 × 10⁶–5.7 × 10¹² viral particles/kg [VP/kg]) of Ad expressing β-galactosidase or saline. CYP protein, activity, gene expression, and serum creatinine (SCr) were evaluated 0.25, 1, 4, and 14 days later. Doses of 5.7 × 10¹¹ and 5.7 × 10¹² 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 5.7 × 10¹⁰–10¹² 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 5.7 × 10¹⁰–10¹² 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 (∼50%) throughout the study for doses at and below 5.7 × 10¹¹ VP/kg. SCr was increased by a factor of 3 by 5.7 × 10¹² 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.