Formononetin and biochanin A protects against ritonavir induced hepatotoxicity via modulation of NfκB/pAkt signaling molecules

Life Sci. 2018 Nov 15:213:174-182. doi: 10.1016/j.lfs.2018.10.023. Epub 2018 Oct 13.

Abstract

Aims: Ritonavir (RIT) is a human immune deficiency virus (HIV) protease inhibitor (PI) active against HIV-1 and HIV-2. Among various adverse effects of PIs, hepatotoxicity is a very common adverse reaction of RIT which is concentration dependent. Red clover isoflavones are found to possess anti-inflammatory, antioxidant and anti-apoptosis activity. Furthermore, recent studies have demonstrated that these isoflavones can be used to alleviate the side-effects of drugs. Hence, the present study was inquested to ascertain the effect of Formononetin (FMN) and Biochanin A (BCA) on RIT induced hepatotoxicity.

Main methods: Five groups of animals were subjected to treatment as control, toxic control (RIT), third group (RIT + FMN), fourth group (RIT + BCA), the fifth group (RIT + FMN + BCA) and sixth group (FMN + BCA) for 14 days. The animals were evaluated for estimation of liver toxicity markers, inflammatory biomarkers, in-vivo biochemical antioxidant parameters. The liver tissues were further evaluated histopathologically and western blotting examination for localization of apoptotic gene expression that plays a pivotal role in hepatotoxicity.

Key findings: FMN and BCA ameliorated the increased levels of biochemical markers of liver, attenuated the RIT induced Bax, caspase-3, NFκB and eNOS activation and persuaded the Bcl2 and pAkt level. Alteration in the levels of inflammatory markers was also observed in both hepatic tissue and serum.

Significance: FMN and BCA exerts hepatoprotective effect through modulating the oxidative stress, inflammation, apoptosis and reversing the tissue degeneration suggesting its therapeutic role in hepatotoxicity and other hepatocellular diseases.

Keywords: Antiretrovirals; Apoptosis; Hepatotoxicity; Inflammation; Isoflavones.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Apoptosis / drug effects
  • Chemical and Drug Induced Liver Injury / metabolism
  • Genistein / metabolism
  • Genistein / pharmacology*
  • Isoflavones / metabolism
  • Isoflavones / pharmacology*
  • Liver / drug effects
  • Liver / metabolism*
  • Liver Diseases / metabolism
  • Male
  • NF-kappa B / metabolism
  • Oxidative Stress / drug effects
  • Protective Agents / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Ritonavir / adverse effects

Substances

  • Antioxidants
  • Isoflavones
  • NF-kappa B
  • Protective Agents
  • formononetin
  • Genistein
  • Proto-Oncogene Proteins c-akt
  • Ritonavir
  • biochanin A