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Renal pathophysiology after systemic administration of recombinant adenovirus: changes in renal cytochromes P450

Hong T Le1, Michael P Boquet, Erin A Clark

  • 1Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA.

Human Gene Therapy
|October 31, 2006
PubMed

Insights

Recombinant adenovirus (Ad) alters kidney cytochrome P450 (CYP) enzymes, affecting renal function and potentially contributing to Ad toxicity. High Ad doses impacted CYP4A and CYP2E1, and altered serum creatinine levels.

Area of Science:

  • Pharmacology
  • Toxicology
  • Molecular Biology

Background:

  • Recombinant adenovirus (Ad) administration is known to alter hepatic cytochrome P450 (CYP) activity.
  • Renal function and its associated CYP enzymes can influence hepatic CYP activity.
  • The impact of Ad on renal CYP enzymes has not been extensively studied.

Purpose of the Study:

  • To investigate the effect of recombinant adenovirus (Ad) on specific renal CYP enzymes (CYP4A1, CYP4A2, CYP4F1, CYP2E1).
  • To evaluate the correlation between Ad dosage, renal CYP alterations, and markers of renal function.

Main Methods:

  • Male Sprague-Dawley rats received varying intravenous doses of Ad expressing beta-galactosidase.
  • Measurements included renal CYP protein, activity, and gene expression at multiple time points.
  • Serum creatinine (SCr) levels and glomerular filtration were assessed to evaluate renal function.

Main Results:

  • High Ad doses (5.7x10^11 - 5.7x10^12 VP/kg) increased CYP4A protein and CYP4A1 mRNA levels.
  • CYP4A2 gene expression was elevated post-Ad administration, while CYP2E1 activity and expression were suppressed.
  • Renal function markers (SCr) showed dose-dependent changes, with significant reduction at lower doses and increase at the highest dose.

Conclusions:

  • Systemic administration of recombinant Ad significantly alters renal CYP enzyme expression and activity.
  • Changes in renal CYP enzymes, particularly CYP4A and CYP2E1, may be implicated in Ad-induced nephrotoxicity.
  • Further research into renal CYP-mediated pathways is warranted to understand Ad toxicity.

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