Effect of beta-carotene on hepatic cytochrome P-450 in ethanol-fed rats

BACKGROUND: Hepatotoxicity of ethanol is increased by beta-carotene in both rodents and nonhuman primates. Furthermore, in smokers who are also drinkers, beta-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 beta-carotene and ethanol treatment on rodent hepatic cytochromes P-450. METHODS AND RESULTS: Weanling male Sprague-Dawley rats were pair-fed beta-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, beta-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 microM). Beta-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 beta-carotene had no significant effect on either total cytochrome P-450 or CYP1A1/2, CYP2B, CYP3A, and CYP4A2/3 contents. CONCLUSIONS: Beta-carotene potentiates the CYP2E1 induction by ethanol in rat liver and also increases CYP4A1, which may, at least in part, explain the associated hepatotoxicity.