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Effect of β‐Carotene on Hepatic Cytochrome P‐450 in Ethanol‐Fed Rats
Author(s) -
Kessova Irina G.,
Leo Maria A.,
Lieber Charles S.
Publication year - 2001
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2001.tb02360.x
Subject(s) - cyp2e1 , ethanol , cyp3a , carotene , weanling , chemistry , cytochrome p450 , medicine , microsome , endocrinology , blot , hydroxylation , pharmacology , biochemistry , metabolism , biology , enzyme , food science , gene
Background: Hepatotoxicity of ethanol is increased by β‐carotene in both rodents and nonhuman primates. Furthermore, in smokers who are also drinkers, β‐carotene increases the incidence of pulmonary cancer. The hepatotoxicity was associated with proliferation of the membranes of the smooth endoplasmic reticulum, suggesting the involvement of cytochromes P‐450. Therefore, the aim of the present study was to assess the effect of β‐carotene and ethanol treatment on rodent hepatic cytochromes P‐450. Methods and Results: Weanling male Sprague‐Dawley rats were pair‐fed β‐carotene (56.5 mg/l of diet) for 8 weeks, with and without ethanol (Lieber‐DeCarli, 1994 liquid diet). As expected, ethanol increased CYP2E1 (measured by Western blots) from 67 ± 8 to 317 ± 27 densitometric units ( p < 0.001). Furthermore, β‐carotene potentiated the ethanol induction to 442 ± 38 densitometric units ( p < 0.01) with a significant interaction ( p = 0.012). The rise was confirmed by a corresponding increase in the hydroxylation of p‐nitrophenol, a specific substrate for CYP2E1, and by the inhibition with diethyl dithiocarbamate (50 μM). β‐Carotene alone also significantly induced CYP4A1 protein (328 ± 49 vs. 158 ± 17 densitometric units, p < 0.05). The corresponding CYP4A1 mRNA (measured by Northern blots) was also increased ( p < 0.05) and there was a significant interaction of the two treatments ( p = 0.015). The combination of ethanol and β‐carotene had no significant effect on either total cytochrome P‐450 or CYP1A1/2, CYP2B, CYP3A, and CYP4A2/3 contents. Conclusions: β‐Carotene potentiates the CYP2E1 induction by ethanol in rat liver and also increases CYP4A1, which may, at least in part, explain the associated hepatotoxicity.