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Title: Cyclic ethanol metabolism in hypophysectomized rats continuously infused alcohol-containing diets

item BADGER, THOMAS - Arkansas Children'S Nutrition Research Center (ACNC)
item FERGUSON, MATTHEW - Arkansas Children'S Nutrition Research Center (ACNC)
item RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Society of Toxicology
Publication Type: Abstract Only
Publication Acceptance Date: 12/5/2008
Publication Date: 3/1/2009
Citation: Badger, T.M., Ferguson, M.E., Ronis, M.J. 2009. Cyclic ethanol metabolism in hypophysectomized rats continuously infused alcohol-containing diets [abstract]. The Toxicologist. 108(1):30. Abstract No. 148.

Interpretive Summary: Alcoholics have been observed to drink in cyclic patterns (binges) when given free access to alcohol. Similar cyclic patterns of drinking have been observed in pigs and monkeys chronically exposed to alcohol. What drives this behavior is currently unclear. However, when rats and mice are continuously infused ethanol diets via a stomach tube (enteral feeding), surprisingly, no steady state is obtained, and instead cyclic patters of ethanol clearance are observed with high peaks of blood alcohol followed by periods of very low blood alcohol. It is possible that this represents a cyclic pattern of ethanol metabolism with a periodicity of approximately 7 days, which may drive binge drinking behavior to maintain blood ethanol levels (BECs). The molecular mechanisms underlying cyclic BECs remain controversial. It was previously suggested that it was related to altered thyroid function at high BECs, which resulted in reduced basal metabolic rate and reduced breakdown of ethanol in the liver. To test this hypothesis, in the current study, control rats and rats where the pituitary had been surgically removed (hypophysectomy, Hx) were enterally fed with ethanol diets for several weeks. Even though Hx rats are unable to regulate thyroid function since without a pituitary they are unable to make thyroid stimulating hormone (TSH), these rats still had cyclic patterns of BECs. This suggests that the previous thyroid hypothesis is incorrect. The data are consistent with our own previous studies that indicate that cyclic BECs are related to cyclic expression of the liver enzyme alcohol dehydrogenase in response to changes in liver insulin signaling produced as a result of cellular stress at high BECs.

Technical Abstract: Chronic ethanol (EtOH) intake induces hepatic alcohol dehydrogenase (ADH) expression via disruption of insulin signaling in liver (JBC 2006; 281:1126-34). Total enteral nutrition (TEN) is a method of slow and continuous (approx. 23/day) feeding patients through an intragastric tube. Rats fed EtOH-containing diets by TEN continuously for 4 weeks do not attain a constant or steady-state of blood ethanol concentrations (BECs), but rather EtOH fluctuates between 0 and >400 mg/dl due to cyclic EtOH metabolism and excretion of EtOH. French et al. previously proposed that these EtOH pulses were due to altered thyroid function at high blood EtOH concentrations and consequent effects on basal metabolic rate (Am. J. Physiol. 2000; 279:G118-G125). We tested this hypothesis in hypophysectomized (HX) or sham-operated (SO) rats, because the absence of thyroid stimulating hormone (TSH) disrupts thyroid function and we could study EtOH pharmacokinetics in the TEN model in a low thyroid hormone state. We found that while body weight gains were lower (P<0.05) in HX rats, pulsatile BECs did not differ in HX and SO rats. We conclude that metabolism of EtOH in the TEN model is not influenced by thyroid function. Thus, in absence of data to the contrary, we have proposed that pulsatile BECs are produced by cyclic EtOH metabolism caused by time-dependent EtOH pharmacokinetics which initiates inhibition of hepatic insulin signaling that leads to reduced SREBP-1 and disinhibition of Class1 ADH transcription.