Biomedical subjects
Publications and source records attributed to R F Derr.
Alcoholic liver disease is the result of a synergism between ethanol and nutritional factors. Therefore, it follows that the pathogenesis of alcoholic liver disease may be affected by the regulation of the intake of nutrients as well as by the regulation of the intake of ethanol.
A physiological pharmacokinetic model of ethanol metabolism was used to simulate ethanol metabolism in standard, fasted, human males of the white American, white European, black American, and Japanese populations. Gastric ethanol metabolism accounted for only 0.24% of the dose in the several populations. In contrast, hepatic first-pass ethanol metabolism accounted for 3.7-4.2% of the dose. Ethanol elimination by the lung and kidney accounted for 1.3-1.7% of the dose in the several populations. The black American population had a significantly higher maximum blood ethanol concentration and area under the blood ethanol concentration versus time curve than the other populations studied when either a single dose or multiple doses of ethanol were ingested. These increases were due to the presence of a considerable amount of the beta 3 beta 3-alcohol dehydrogenase (ADH) isoenzyme, with a Michaelis constant of 34 mM in the black American population. The Japanese population, which has a relatively high proportion of the beta 2 beta 2-ADH isozyme, metabolized ethanol somewhat more rapidly than the other populations, as previously noted.
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The question of humaneness of decapitation per se has been considered. The time required for the oxygen tension in decapitated rat brain to decline to a level at which the brain becomes unconscious was estimated to be 2.7 sec. Assuming that decapitation is a powerful arousal stimulus and that the resulting EEG activation (low voltage, fast activity) indicates a conscious awareness of pain and distress the maximum time the pain and distress could be perceived would be 2.7 sec. Hence, decapitation of rats per se may be considered humane.
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Ingestion of various liquid diets containing 36% calories as ethanol and 35% calories as fat does not provide adequate nutrition to young growing rats. Studies conducted with the aforementioned diets have the effects of malnutrition confounded with those of alcohol administration. Feeding a 26% alcohol liquid diet, which results in adequate nutrient intake with the same level of alcohol ingestion as the 36% alcohol diet, does not result in fatty liver development in the rat. The concept that prevailed for 25 years that fatty liver is caused despite adequate nutrition and hence is due to alcohol alone is therefore erroneous.
The alcohol withdrawal syndrome consists of a kinetic tremor, the tremorous component, and a peculiar abnormality of tone called asterixis, the muscular rigidity component. The severity of the ethanol withdrawal syndrome in the rat is generally assessed by the severity of the tremors. 3-Hydroxybutyrate suppresses the tremorous component but not the muscular rigidity component of the ethanol withdrawal syndrome, thus effectively differentiating the two components in the rat.
Our present understanding of the many effects of chronic ethanol consumption originated mostly from the use of an experimental model in which animals were maintained on a liquid diet that provided 36% of the total calories as alcohol. Since this diet was considered to be nutritionally adequate, a concept developed that the observed effects were due to the toxicity of alcohol and its metabolites rather than malnutrition. However, several biologic effects can be attributed to a reduced carbohydrate ingestion that accompanies chronic alcohol consumption.
An ethanol withdrawal syndrome was elicited by withholding ethanol from physically dependent, male Sprague-Dawley rats. Ethanol dependence had been induced by intragastric administration of ethanol at a dosage of 9 to 15 grams per kilogram per day over a four-day period. Oral administration of 3-hydroxybutyrate, a compound which is elevated in blood of ethanol dependent rats and is a substrate of both the cerebral small-pool and large-pool Krebs-cycle, was effective in suppressing the tremulous component of the ethanol withdrawal syndrome. 3-Hydroxybutyrate did not function as a central nervous system depressant at the dose levels employed.
The hypothesis is advanced that the ethanol withdrawal syndrome is a manifestation of dependence by a cerebral Krebs-cycle on substrates which are readily available during ethanol addiction but which are relatively unavailable during withdrawal.
Increasing the caloric density in an ethanol containing drinking fluid from that of 3.2% ethanol alone, 0.18 kcal/ml, 2.33-fold to 0.42 kcal/ml with the addition of lactose and glycerol, did not significantly alter ethanol consumption. Increasing the caloric density of the drinking fluid to 0.56 kcal/ml significantly reduced ethanol consumption. The decrease in ethanol consumption was neither due to the taste of the added glycerol and lactose nor to the total caloric content of the solution but rather to an interaction between ethanol and caloric density. Increasing the caloric density of the solid diet and adding a feeding stimulant, sucrose, significantly decreased 3.2% ethanol consumption.
The first order rate constant for the conversion of intraperitoneally administered methanethiol to sulfate in the rat was found to be 0.571 hr-1. The first order rate constant for the urinary excretion of sulfate was 0.0818 hr-1. Thus, the half-life for the metabolism of methanethiol to sulfate was 1.21 hr and for the elimination of sulfate in the urine was 8.47 hr.
Butyrate, lactate and beta-hydroxybutyrate, compounds which may be elevated in blood of ethanol dependent rats and substrates of the cerebral small-pool Krebs-cycle, were tested for their ability to suppress an ethanol withdrawal syndrome. Male Sprague-Dawley rats were rendered physically dependent on ethanol by intragastric administration of ethanol at a dosage of 9 to 15 grams per kilogram per day over a 4-day period. Oral administration of a mixture of butyrate, lactate and beta-hydroxybutyrate was effective in suppressing the tremulous component of the ethanol withdrawal syndrome.
Methanethiol is associated with hepatic failure in humans and the synergistic action of methanethiol, ammonia and octanoate is sufficient to account for the coma of experimental hepatic necrosis. The sulfur atom of methanethiol is eliminated from the body as urinary sulfate at a rate which is approximated by a hyperbola such that 94% is excreted within 21 h after administration. Rats in octanoate or hepatic coma excreted only little sulfate in their urine.
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