Diet and risk of ethanol-induced hepatotoxicity: Carbohydrate-fat relationships in rats

Nutritional status is a primary factor in the effects of xenobiotics and ma y be an important consideration in development of safety standards and asse ssment of risk. One important xenobiotic consumed daily by millions of peop le worldwide is alcohol. Some adverse effects of ethanol, such as alcohol l iver disease, have been linked to diet. For example, ethanol-induced hepato toxicity in animal models requires diets that have a high percentage of the total calories as unsaturated fat. However, little attention has been give n to the role of carbohydrates (or carbohydrate to fat ratio) in the effect s of this important xenobiotic on liver injury. In the present study, adult male Sprague-Dawley rats (8-10/group) were infused (intragastrically) diet s high in unsaturated fat (25 or 45% total calories), sufficient protein (1 6%) 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 ad equate in carbohydrate developed steatosis, but had no other signs of hepat ic pathology. However, rats infused with the carbohydrate-deficient diet ha d a 4-fold increase in serum ALT levels (p < 0.05), an unexpectedly high (3 4-fold) induction of hepatic microsomal CYP2E1 apoprotein (p < 0.001), and focal necrosis. The strong positive association between low dietary carbohy drate, enhanced CYP2E1 induction and hepatic necrosis suggests that in the presence of low carbohydrate intake, ethanol induction of CYP2E1 is enhance d to levels sufficient to cause necrosis, possibly through reactive oxygen species and other free radicals generated by CYP2E1 metabolism of ethanol a nd unsaturated fatty acids.