Chlormethiazole treatment prevents reduced hepatic vitamin A levels in ethanol-fed rats.
BACKGROUND
Chronic ethanol intake results in decreased hepatic vitamin A levels through both enhanced degradation of vitamin A via a cytochrome P450 enzyme (CYP)-dependent process and increased mobilization of vitamin A from the liver into the circulation. This study investigated whether treatment with chlormethiazole, a CYP inhibitor, restores vitamin A in the livers of ethanol-fed rats.


METHODS
Ethanol-exposed and non-ethanol-exposed rats were treated with or without chlormethiazole (10 and 100 mg/kg body weight) for 1 month. Liver and plasma levels of retinol and retinyl palmitate were analyzed by high-performance liquid chromatography. Expressions of hepatic lecithin:retinol acyltransferase (LRAT) and cellular retinol-binding protein were analyzed with reverse transcription-polymerase chain reaction. Hepatic retinol esterification by LRAT was examined by using incubations of the microsomal fractions of livers with exogenous sources of retinol.


RESULTS
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. Furthermore, increased plasma concentrations of retinyl palmitate in rats fed with ethanol, which indicate increased mobilization of vitamin A, were partially inhibited by chlormethiazole treatment. However, neither ethanol nor chlormethiazole treatment altered the expression and activity of LRAT in the liver of rats. Hepatic expression of cellular retinol-binding protein increased significantly in ethanol-fed rats with or without chlormethiazole treatment compared with control rats.


CONCLUSIONS
These data suggest that chlormethiazole can restore both hepatic retinol and retinyl ester concentrations to normal levels in ethanol-fed rats through blocking enhanced both degradation of vitamin A and mobilization of vitamin A from the liver into the circulation.
Liu
Chun
C
Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA.
Chung
Jayong
J
Seitz
Helmut K
HK
Russell
Robert M
RM
Wang
Xiang-Dong
XD
D000428:Alcohol Drinking / Q000009:adverse effects / Q000378:metabolism; D000818:Animals; D002719:Chlormethiazole / Q000494:pharmacology* / Q000627:therapeutic use; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D000084562:Retinyl Esters; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014802:Vitamin A Deficiency / Q000139:chemically induced* / Q000517:prevention & control*
D004224:Diterpenes; D000084562:Retinyl Esters; D002719:Chlormethiazole; D014801:Vitamin A; C014794:retinol palmitate; D000431:Ethanol