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. 2000 Dec;47(6):825–831. doi: 10.1136/gut.47.6.825

Inhibition of retinol oxidation by ethanol in the rat liver and colon

A Parlesak 1, I Menzl 1, A Feuchter 1, J Bode 1, C Bode 1
PMCID: PMC1728129  PMID: 11076882

Abstract

BACKGROUND—Epidemiological evidence has been presented for an increased risk of development of colon cancer after chronic alcohol abuse. Alcohol is degraded by cytosolic alcohol dehydrogenases that also are capable of retinol oxidation. Inhibition of retinol oxidation to retinoic acid has been shown to occur in parallel with profound impairment of intracellular retinoid signal transduction and loss of cell differentiation control.
AIMS—In the present study, the change in cytosolic retinol oxidation and retinoic acid formation by ethanol concentrations that occur in body tissues in humans after social drinking was measured in cells from the liver, and small and large intestine of the rat.
RESULTS—The specific catalytic efficiency Vmax/Km (ml/min/g) of cytosolic retinol oxidation in the large intestine (28.9) was found to be distinctly higher than that in the liver (3.4), while the efficiency in the small intestine was negligible (0.20). In the presence of increasing ethanol concentrations (9, 17, and 34 mM), Vmax/Km for retinol oxidation decreased in a dose dependent manner to 7.8% of the initial value in the large intestine and to 12% in the liver. The Vmax/Km of retinoic acid formation in the liver cytosol decreased to 15%.
CONCLUSIONS—Our data demonstrate impairment of hepatic and intestinal cytosolic retinol oxidation and retinoic acid formation by ethanol at concentrations in body tissues after social drinking in humans. The results suggest that the increased risk of developing colorectal neoplasias after alcohol abuse may, at least in part, be caused by impaired retinoid signal transduction.


Keywords: retinol; retinoic acid; ethanol; alcohol; alcohol dehydrogenases; intestine

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Figure 1  .

Figure 1  

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Effect of different ethanol concentrations (without (w/o) alcohol, and 8.6 mM, 17 mM, and 34 mM ethanol) on cytosolic (c) retinol dehydrogenase activity in the liver (A) and large intestine (B). In both organs, retinol oxidation is inhibited by increasing ethanol concentration in a dose dependent manner.

Figure 2  .

Figure 2  

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After reverse phase separation, the internal standard (4-(1,1,3,3 tetramethylbutyl)-phenol solution; TMBP 2.26/2.20 minutes at 276 nm) and retinol (6.25/6.04 minutes at 326 nm) were quantified in the first channel of the diode array detector (upper chromatogram) while retinoic acid (2.87/2.78 minutes at 340 nm) and retinal (7.76/7.50 minutes at 382 nm) were measured in the second one (lower chromatogram). The HPLC chromatograms resulted from incubation (20 minutes, 37° C) of a buffered retinol solution (140 mM) with 4 mM NAD+ in the presence of 10% (v/v) cytosolic fraction obtained from rat mucosa cells without ethanol (A) and with 0.2% ethanol (B). Ethanol significantly inhibited the amount of formed retinal while the concentration of retinoic acid remained at levels which also occurred in control assays without cytosol. For calculation of enzyme kinetics, differences between concentrations found in the experiments with cytosol and blank incubations were applied.

Figure 3  .

Figure 3  

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Retinoic acid formation in hepatic cytosol of the rat at different ethanol concentrations (without (w/o) alcohol, and 8.6 mM, 17 mM, and 34 mM ethanol). The ethanol associated inhibition of enzyme activity, which is related to the concentration of the applied retinol concentration, is in parallel with overall retinol oxidation.

Figure 4  .

Figure 4  

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Retinoic acid formation in the hepatic cytosol of the rat shown at different ethanol concentrations (without (w/o) alcohol, and 8.6 mM, 17 mM, and 34 mM ethanol) is dependent on the average intermediary formed retinal concentration. The reduction in retinoic acid formation from retinal by ethanol indicates ethanol induced reduction of retinal oxidation in addition to impairment of retinol oxidation.

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