Nicotine enhances alcoholic fatty liver in mice: Role of CYP2A5.

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 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 produced during the process of CYP2A5-dependent nicotine metabolism.

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