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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #136039
Title: CHLORMETHIAZOLE TREATMENT PREVENTS REDUCED VITAMIN A LEVELS IN ETHANOL-FED RATS

Author
item LIU, CHUN - HNRCA
item CHING, JAYONG - HNRCA
item SEITZ, HELMUT - SALEM MEDICAL CENTER
item RUSSELL, ROBERT - HNRCA
item WANG, XIANG-DONG - HNRCA

Submitted to: Alcoholism: Clinical and Experimental
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/6/2002
Publication Date: 11/1/2002
Citation: LIU, C., CHING, J., SEITZ, H.K., RUSSELL, R.M., WANG, X. CHLORMETHIAZOLE TREATMENT PREVENTS REDUCED VITAMIN A LEVELS IN ETHANOL-FED RATS. ALCOHOLISM: CLINICAL AND EXPERIMENTAL. 2002;26:1730-1709.

Interpretive Summary: Chronic alcohol intake results in decreased liver vitamin A levels through enhanced degradation of vitamin A via an enzyme (cytochrome P450 enzymes) dependent process. We investigated whether treatment with chlormethiazole, a cytochrome P450 enzymes inhibitor, restores vitamin A in the livers of ethanol-fed rats. Results showed that the treatment with chlormethiazole at two different doses in ethanol-fed rats completely blocked the formation of hepatic vitamin A polar metabolites and restored hepatic levels of vitamin A in a dose-dependent manner. These data suggest that alchol-reduced hepatic vitamin A levels are due to enhanced degradation of vitamin A and "leakage" of vitamin A from the liver into the circulation. Chlormethiazole can restore liver vitamin A to normal levels in ethanol-fed rats, which may offer a useful approach to prevent alcohol impaired vitamin A status.

Technical Abstract: Chronic ethanol intake results in decreased hepatic vitamin A levels trhough enhanced degradation of vitamin A via a cytochrome P450 enzyme (CYP) dependent process. The aim of this study is to investigate whether treatment with chlormethiazole, a CYP inhibitor, restores vitamin A in the livers of ethanol-fed rats. Both ethanol-exposed or non-ethano-exposed rats were treated with or without chlormethiazole (10 mg and 100 mig/kg BW) for one month. Liver and plasma levels of retinol and retnyl palmitate were analyzed by high-performance liquid chromatography (HPLC). Expressions of hepatic lecithin:retinol acyltransferase (LRAT) and cellular retinol binding protein (CRBP) were analyzed using reverse transcription-polymerase chain reaction (RT-PCR). Hepatic retinol esterification by LRAT was examined using in vitro incubations of the microsomal fractions of livers. Ethanol-feeding in rats for a month resulted in lower hepatic levels of retinol and retinyl palmitate than those found in controls and the occurrence of several polar retinoid metabolites. In contrast, treatment with chlormethiazole at two different doses in ethanol-fed rats completely blocked the formation of hepatic retinoid polar metabolites and restored hepatic levels of retinol and hepatic retinyl palmitate in a dose-dependent manner. Elevated plasma concentrations of retinyl palmitate in rats fed with ethanol were partially inhibited by chlormethiazole treatment. Neither ethanol nor chlormethiazole treatment altered the expression and the activity of LRAT in the liver of rats. These data suggest that ethanol-reduced hepatic vitamin A levels are due to enhanced degradation of vitamin A and "leakage" of vitamin A from the liver into the circulation rather than impaired LRAT activity. Chlormethiazole can restore both hepatic retinol and retinyl ester concentrations to normal levels in ethanol-fed rats in vivo, which may offer a useful approach to prevent ethanol-impaired vitamin A status.