Nicotine enhances alcoholic fatty liver in mice: Role of CYP2A5

Abstract

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.

Suppressed hepatocyte proliferation via a ROS-HNE-P21 pathway is associated with nicotine- and cotinine-enhanced alcoholic fatty liver in mice

“…LPO end product HNE inhibits cell proliferation (34,35). Under metabolism by CYP2A5, both nicotine and cotinine can produce ROS and enhance formation of MDA, another LPO end product, which was observed in WT mice but not in KO mice (21). Here we further detected HNE.…”

“…Previously we reported that nicotine and cotinine enhanced alcoholic fatty liver in WT mice but not in KO mice as evaluated by Hematoxylin & Eosin staining, Oil Red O staining, and liver triglyceride (TG) biochemical measurement (21). To further identify the mechanisms by which nicotine and cotinine enhance alcoholic fatty liver, differential gene expression analysis was performed using the RNA sequencing data.…”

“…Nicotine, a major stimulant and addiction-forming alkaloid in tobacco smoke, can also enhance alcoholic fatty liver in mice but it didn't enhance alcohol-induced liver inflammation (20). Recently we found that cotinine, a major metabolite of nicotine can also enhance alcoholic fatty liver, and nicotine-and cotinine-enhanced alcoholic fatty liver were not observed in CYP2A5 knockout (KO) mice while the fatty liver was enhanced in CYP2A5 wild type (WT) mice, suggesting a pivotal role of CYP2A5 (21).…”

“…Oxidative stress is identified as a mechanism involved in the inhibited regeneration of fatty livers (25). During nicotine and cotinine metabolism, CYP2A5-dependent reactive oxygen species (ROS) generation and lipid peroxidation (LPO) might contribute to the CYP2A5-dependent enhancing effects (21). In this study, we performed liver differential gene expression analyses from RNA-seq data.…”

The Impact of Sex on Changes in Plasma Corticosterone and Cotinine Levels Induced by Nicotine in C57BL/6J Mice

“…CYP2A5 is induced by a variety of chemicals, and it is generally accepted that a common factor among them is the production of reactive oxygen species, which causes oxidative stress in the liver [ 20 , 21 ]. Recently, Chen and colleagues [ 22 ] reported that production of the reactive oxygen species increased by 4-fold upon incubation of microsomes from CYP2A5+/+ mice with nicotine or cotinine, whereas microsomes from CYP2A5−/− mice did not produce any reactive oxygen species. Metabolism of nicotine to cotinine requires two oxidation reactions, namely, the formation of nicotine-∆5′(1′)-iminium ion and its conversion to cotinine.…”