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Cyclosporine-induced changes in drug metabolizing enzymes in hyperlipemic rabbit kidneys could explain its toxicity

Fawzy Elbarbry1, Ahmed Ragheb, Ahmed Attia

  • 1School of Pharmacy, Pacific University Oregon, Hillsboro, OR, USA.

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
|September 16, 2010
PubMed

Insights

Cyclosporine A (CsA) increases kidney reactive oxygen species (ROS) and CYP2E1 activity, causing damage. Hyperlipidemia reduces CsA-induced kidney injury by normalizing ROS, but not CYP2E1 levels.

Area of Science:

  • Nephrology
  • Pharmacology
  • Toxicology

Background:

  • Cyclosporine A (CsA) is a vital immunosuppressant with known nephrotoxicity.
  • The precise mechanisms underlying CsA-induced kidney damage, particularly the role of drug-metabolizing enzymes and oxidative stress, require further elucidation.
  • Hyperlipidemia's influence on CsA nephrotoxicity is not well understood.

Purpose of the Study:

  • To investigate the role of Cytochrome P450 2E1 (CYP2E1) and reactive oxygen species (ROS) in CsA-mediated nephrotoxicity.
  • To determine the effect of hyperlipidemia on CsA-induced kidney injury in a rabbit model.
  • To explore the interplay between CsA, hyperlipidemia, CYP2E1, and oxidative stress in the kidney.

Main Methods:

  • A hyperlipemic rabbit model was established using a high-cholesterol diet.
  • Rabbits were divided into four groups: control diet, high-cholesterol diet, CsA treatment, and high-cholesterol diet with CsA.
  • Kidney microsomes were analyzed for CYP2E1 activity, ROS markers (malondialdehyde, protein carbonyl), and antioxidant proteins.

Main Results:

  • CsA significantly increased kidney malondialdehyde, protein carbonyl, and CYP2E1 activity.
  • A high-cholesterol diet alone did not induce these changes.
  • Co-administration of CsA and a high-cholesterol diet normalized ROS markers and significantly reduced tubular injury compared to CsA alone, without altering CsA-induced CYP2E1 activity.

Conclusions:

  • CsA enhances renal ROS production and CYP2E1 activity, contributing to nephrotoxicity.
  • Hyperlipidemia attenuates CsA-induced tubular injury, likely by normalizing renal ROS levels.
  • The protective effect of hyperlipidemia against CsA nephrotoxicity is independent of its effect on CYP2E1 activity.

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