Toxicological Sciences, Vol 47, 110-117, Copyright © 1999 by Society of Toxicology
S Korourian, R Hakkak, MJ Ronis, SR Shelnutt, J Waldron, M Ingelman-Sundberg and TM Badger
Nutritional status is a primary factor in the effects of xenobiotics and
may be an important consideration in development of safety standards and
assessment of risk. One important xenobiotic consumed daily by millions of
people worldwide is alcohol. Some adverse effects of ethanol, such as
alcohol liver disease, have been linked to diet. For example,
ethanol-induced hepatotoxicity in animal models requires diets that have a
high percentage of the total calories as unsaturated fat. However, little
attention has been given to the role of carbohydrates (or carbohydrate to
fat ratio) in the effects of this important xenobiotic on liver injury. In
the present study, adult male Sprague-Dawley rats (8-10/group) were infused
(intragastrically) diets high in unsaturated fat (25 or 45% total
calories), sufficient protein (16%) and ethanol (38%) in the presence or
absence of adequate carbohydrate (21 or 2.5%) for 42-55 days (d). Animals
infused ethanol- containing diets adequate in carbohydrate developed
steatosis, but had no other signs of hepatic pathology. However, rats
infused with the carbohydrate-deficient diet had a 4-fold increase in serum
ALT levels (p < 0.05), an unexpectedly high (34-fold) induction of
hepatic microsomal CYP2E1 apoprotein (p < 0.001), and focal necrosis.
The strong positive association between low dietary carbohydrate, enhanced
CYP2E1 induction and hepatic necrosis suggests that in the presence of low
carbohydrate intake, ethanol induction of CYP2E1 is enhanced to levels
sufficient to cause necrosis, possibly through reactive oxygen species and
other free radicals generated by CYP2E1 metabolism of ethanol and
unsaturated fatty acids.
ARTICLES
Diet and risk of ethanol-induced hepatotoxicity: carbohydrate-fat relationships in rats
Department of Pediatrics, University of Arkansas for Medical Services, Little Rock, USA.
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