D-limonene suppresses doxorubicin-induced oxidative stress and inflammation via repression of COX-2, iNOS, and NFκB in kidneys of Wistar rats

Exp Biol Med (Maywood). 2014 Apr;239(4):465-76. doi: 10.1177/1535370213520112. Epub 2014 Feb 28.


D-limonene is a naturally occurring monoterpene and has been found to posses numerous therapeutic properties. In this study, we used D-limonene as a protective agent against the nephrotoxic effects of anticancer drug doxorubicin (Dox). Rats were given D-limonene at doses of 5% and 10% mixed with diet for 20 consecutive days. Dox was give at the dose of 20 mg/kg body weight intraperitoneally. The protective effects of D-limonene on Dox-induced oxidative stress and inflammation were investigated by assaying oxidative stress biomarkers, lipid peroxidation, serum toxicity markers, proinflammatory cytokines, and expression of nuclear factor kappa B (NFκB), cyclo-oxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) and Nitrite levels. Administration of Dox (20 mg/kg body weight) in rats enhanced renal lipid peroxidation; depleted glutathione content and anti-oxidant enzymes; elevated levels of kidney toxicity markers viz. kidney injury molecule-1 (KIM-1), blood urea nitrogen (BUN), and creatinine; enhanced expression of NFκB, COX-2, and iNOS and nitric oxide. Treatment with D-limonene prevented oxidative stress by restoring the levels of antioxidant enzymes, further both doses of 5% and 10% showed significant decrease in inflammatory response. Both the doses of D-limonene significantly decreased the levels of kidney toxicity markers KIM-1, BUN, and creatinine. D-limonene also effectively decreased the Dox induced overexpression of NF-κB, COX-2, and iNOS and nitric oxide. Data from the present study indicate the protective role of D-limonene against Dox-induced renal damage.

Keywords: d-limonene; Chemoprevention; doxorubicin; nephrotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Biomarkers / blood
  • Cyclohexenes / pharmacology*
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Cytokines / metabolism
  • Doxorubicin / toxicity*
  • Glutathione / metabolism
  • Kidney / drug effects*
  • Kidney / metabolism
  • Limonene
  • Lipid Peroxidation
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism*
  • Nitrites / metabolism
  • Oxidative Stress / drug effects*
  • Protective Agents / pharmacology*
  • Rats
  • Rats, Wistar
  • Terpenes / pharmacology*


  • Antioxidants
  • Biomarkers
  • Cyclohexenes
  • Cytokines
  • NF-kappa B
  • Nitrites
  • Protective Agents
  • Terpenes
  • Doxorubicin
  • Limonene
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • Glutathione