Nicotine enhances alcoholic fatty liver in mice: Role of CYP2A5

Arch Biochem Biophys. 2018 Nov 1;657:65-73. doi: 10.1016/ Epub 2018 Sep 15.


Tobacco and alcohol are often co-abused. Nicotine can enhance alcoholic fatty liver, and CYP2A6 (CYP2A5 in mice), a major metabolism enzyme for nicotine, can be induced by alcohol. CYP2A5 knockout (cyp2a5-/-) mice and their littermates (cyp2a5+/+) were used to test whether CYP2A5 has an effect on nicotine-enhanced alcoholic fatty liver. The results showed that alcoholic fatty liver was enhanced by nicotine in cyp2a5+/+ mice but not in the cyp2a5-/- mice. Combination of ethanol and nicotine increased serum triglyceride in cyp2a5+/+ mice but not in the cyp2a5-/- mice. Cotinine, a major metabolite of nicotine, also enhanced alcoholic fatty liver, which was also observed in cyp2a5+/+ mice but not in the cyp2a5-/- mice. Nitrotyrosine and malondialdehyde (MDA), markers of oxidative/nitrosative stress, were induced by alcohol and were further increased by nicotine and cotinine in cyp2a5+/+ mice but not in the cyp2a5-/- mice. Reactive oxygen species (ROS) production during microsomal metabolism of nicotine and cotinine was increased in microsomes from cyp2a5+/+ mice but not in microsomes from cyp2a5-/- mice. These results suggest that nicotine enhances alcoholic fatty liver in a CYP2A5-dependent manner, which is related to ROS produced during the process of CYP2A5-dependent nicotine metabolism.

Keywords: CYP2A6; Cotinine; Metabolism; Oxidative stress; Reactive oxygen species; Triglyceride.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / metabolism
  • Cotinine / adverse effects
  • Cotinine / blood
  • Cotinine / metabolism
  • Cotinine / urine
  • Cytochrome P450 Family 2 / genetics
  • Cytochrome P450 Family 2 / metabolism*
  • Ethanol / toxicity
  • Fatty Liver, Alcoholic / etiology*
  • Fatty Liver, Alcoholic / metabolism
  • Female
  • Gene Knockout Techniques
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microsomes, Liver / metabolism
  • Nicotine / adverse effects*
  • Nicotine / metabolism*
  • Oxidative Stress / drug effects
  • Reactive Oxygen Species / metabolism


  • Reactive Oxygen Species
  • Ethanol
  • Nicotine
  • Aryl Hydrocarbon Hydroxylases
  • Cyp2a5 protein, mouse
  • Cytochrome P450 Family 2
  • Cotinine