Alcohol detoxification accelerated by oxygenated drinking water.

The liver eliminates ethanol through several oxygen dependent processes. Since the liver receives most of its blood flow through the portal vein, it should be possible to increase its oxygen tension by augmenting the oxygen saturation of the portal vein. We therefore studied elimination of ethanol administered intravenously to three monkeys who received strongly oxygenated drinks at 20 to 30 minute intervals during the whole experiment. From these drinks dissolved oxygen was presumably released in the stomach and upper intestine and arrived to the liver along the portal vein. As a consequence of this treatment the elimination rate of ethanol increased 60 % on the average. The increase was significant on the level of p < 0.02. The production of acetaldehyde also increased but less significantly. Measurements of oxygen tensions in the portal blood of two anaesthetized dogs indicated 7 and 8 % increases lasting for 10 and 15 minutes after infusion of oxygenated water into the stomach.     

In vivo ethanol elimination in man, monkey and rat: a lack of relationship between the ethanol metabolism and the hepatic activities of alcohol and aldehyde dehydrogenases

The in vivo ethanol elimination in human subjects, monkeys and rats was investigated after an oral ethanol dosage. After 0.4 g. ethanol/kg of body weight, ethanol elimination was much slower in human subjects than in monkeys. In order to detect a rise in monkey plasma ethanol concentrations as early as observed in human subjects, ethanol had to be administered at a dose of 3 g/kg body weight. Ethanol metabolism in rats was also much faster than in human subjects. However, human liver showed higher alcohol dehydrogenase activity and higher low Km aldehyde dehydrogenase activity than rat liver. Thus, our data suggest a lack of relationship between hepatic ethanol-metabolizing activities and the in vivo ethanol elimination rate.     

Ferment in the family tree: does a frugivorous dietary heritage influence contemporary patterns of human ethanol use?

Humans and apes are placed together in the superfamily Hominoidea. The evolutionary trajectory of hominoids is intimately bound up with the exploitation of ripe, fleshy fruits. Fermentation of fruit sugars by yeasts produces a number of alcohols, particularly ethanol. Because of their pre-human frugivorous dietary heritage, it has been hypothesized that humans may show pre-existing sensory biases associating ethanol with nutritional rewards. This factor, in turn, could influence contemporary patterns of human ethanol use. At present, there seems little evidence to support a view of selection specifically for ethanol detection or its utilization over the course of hominoid evolution. Ethanol concentration in wild fruits consumed by monkeys and apes is predicted to be low. Wild monkeys and apes avoid consumption of over-ripe fruits, the class showing notable ethanol concentrations, and for this reason, ethanol plumes may act as deterrents rather than attractants. Any energetic benefits to wild primates from ingested ethanol appear negligible, at best. Mice and rats show patterns of ethanol self-administration similar to humans, indicating that a frugivorous dietary heritage is not necessary for such behaviors. In the natural environment, ethanol is predicted to be just one of many alcohols, esters and related compounds routinely encountered by frugivorous primates and of no particular significance. The strong attraction ethanol holds for some individuals could be due to a broad range of genetic and environmental factors. In some humans, the appetite for ethanol appears related to the appetite for sugar. The predisposition some individuals display toward excessive ethanol consumption could involve features of their genetics and biochemical similarities of ethanol and carbohydrate. Regular low ethanol intake is hypothesized to lower the incidence of cardiovascular disease in humans, perhaps through its effects on body fat distribution. Such a benefit, if confirmed, would appear to relate to features of the contemporary human rather than pre-human diet.     

Sex differences in total body water in adolescent rhesus macaques estimated by ethanol dilution

Abstract: Non‐human primates are widely used in research, yet relatively few studies have addressed potential pharmacokinetic differences between males and females. The present study examined the relationship between total body water, sex, age, and weight in the rhesus macaque (Macaca mulatta). Ethanol‐naïve, adolescent rhesus macaques (n = 119) were administered ethanol (males, 2.1 g/kg; females, 2.0 g/kg) intravenously, and blood samples for blood ethanol concentration obtained at 5, 10, and 60 minutes following the end of the infusion. Non‐linear regression was used to compare and contrast a series of pharmacokinetic models examining the relationship between weight, sex, age, V_d and zero‐order elimination rate. V_d (mean ± SEM) for male rhesus was 0.771 ± 0.008 l/kg and for females was 0.730 ± 0.008 l/kg, different at P < 0.00001. There were no sex differences in the rate of zero‐order ethanol elimination, estimated to be 0.0032 ± 0.0004 g/kg/minute. The data reported here may be useful in designing and interpreting pharmacokinetic studies using rhesus monkeys.     

Cortisol metabolism in the Bolivian squirrel monkey (Saimiri boliviensis boliviensis)

New World squirrel monkeys (Saimiri spp.) have high circulating cortisol levels but normal electrolytes and blood pressures. The goal of the present study was to gain insight into adaptive mechanisms used by Bolivian squirrel monkeys to minimize the effects of high cortisol on mineralocorticoid receptor (MR) activity and electrolyte and water balance. Aldosterone levels in serum from 10 squirrel monkeys were 17.7 +/- 3.4 ng/dl (normal range in humans, 4 to 31 ng/dl), suggesting that squirrel monkeys do not exhibit a compensatory increase in aldosterone. The squirrel monkey MR was cloned and expressed in COS-7 cells and found to have similar responsiveness to cortisol and aldosterone as human MR, suggesting that squirrel monkey MR is not inherently less responsive to cortisol. To determine whether altered metabolism of cortisol might contribute to MR protection in squirrel monkeys, serum and urinary cortisol and cortisone were measured, and a comprehensive urinary corticosteroid metabolite profile was performed in samples from anesthetized and awake squirrel monkeys. The levels of cortisone exceeded those of cortisol in serum and urine, suggesting increased peripheral 11beta-hydroxysteroid dehydrogenase 2 activity in squirrel monkeys. In addition, a significant fraction (approximately 20%) of total corticosteroids excreted in the urine of squirrel monkeys appeared as 6beta-hydroxycortisol, compared with that in man (1%). Therefore, changes in cortisol metabolism likely contribute to adaptive mechanisms used by Bolivian squirrel monkeys to minimize effects of high cortisol.     

Effects of ethanol, fructose, and ethanol plus fructose infusions on plasma glucose concentration and glucose turnover in monkeys (Macaca fascicularis) as measured by [6-3H]glucose

Six adult, female, cynomolgus monkeys were fasted for 64 hr and then continuously infused with [6-3H]glucose to determine the rates of glucose turnover and clearance while they were also being infused with ethanol (110 mumol/min/kg), 1,3-butanediol (110 mumol/min/kg), fructose (30 mumol/min/kg) or ethanol plus fructose (110 and 30 mumol/min/kg) respectively. Both ethanol and 1,3-butanediol infusions decreased the glucose turnover rate (the steady-state input-output rate from the plasma glucose pool) and the plasma glucose concentration by halving the glucose production rate. In contrast, fructose infusions increased the glucose turnover rate and glucose concentration by increasing the glucose production rate by 20%. The plasma clearance rate of glucose was lowest when the animals were infused with ethanol plus fructose; this suggests that acetate from ethanol oxidation may have a glucose-sparing effect if normoglycemia is maintained.     

Liver alcohol dehydrogenase activity in the female rat: Effects of ovariectomy and estradiol administration

The effects of ovariectomy and administration of estradiol on the activity of liver alcohol dehydrogenase and on the rate of ethanol elimination were determined in female Sprague-Dawley rats. The activity of the enzyme and the rates of ethanol elimination in the female sham-operated animals were higher than obtained previously in male rats of the same age. Ovariectomy had no effect on liver alcohol dehydrogenase and on rates of ethanol elimination. Estradiol administration resulted in an increase in liver weight and in total liver alcohol dehydrogenase activity per animal in sham-operated but not in ovariectomized animals. The increase in enzyme activity after estradiol administration in sham-operated animals was not associated with a significant increase in the rate of ethanol elimination, suggesting that the enzyme activity in female rats is not rate-limiting in in vivo ethanol oxidation.     

Ethanol drinking by vervet monkeys (Cercopithecus pygerethrus): individual responses of juvenile and adult males

Unrestricted access of vervet monkeys to a palatable solution of ethanol resulted in chronic intake or abstinence. Self-selected dose averaged 4.42 g/kg body mass/day. Growth of juveniles was not grossly affected. In plasma, chronic ethanol intake was associated with lower average K and Cl values, increased gamma glutamyl transpeptidase in some adults, and higher average total cholesterol. Neither hepatic histology nor haematology were affected by chronic ethanol intake.     

Action of intragastric ethanol on pancreatic exocrine secretion in relation to the interdigestive gastrointestinal motility in humans

On different days, fasted volunteers were given either 100 ml of ethanol (40% v/v), glucose (isocaloric to ethanol) or distilled water intragastrically; the instillations always starting during the first observed duodenal phase I of the interdigestive migrating complex (IMC). Both ethanol and glucose produced a fed pattern of motility but only glucose significantly (P less than 0.05) delayed the reappearance of a new duodenal phase III of the IMC when compared to water. Ethanol and glucose significantly increased the 1-h duodenal bicarbonate output 7- and 16-fold, respectively. Glucose, but not ethanol, stimulated the duodenal amylase output when compared to water. Glucose, but not ethanol, caused a significant rise in plasma gastrin concentration; plasma secretin levels not being altered by both substances. We conclude that in non-alcoholic humans, an intragastric administration of ethanol in a concentration present in whisky and in an amount that is consumed in ordinary social drinking has a weak stimulatory action on pancreatic bicarbonate secretion and that this action is not mediated by release of secretin.     

Identification of P-450ALC in microsomes from alcohol dehydrogenase-deficient deermice: contribution to ethanol elimination in vivo

Isozyme 3a of rabbit hepatic cytochrome P-450, also termed P-450ALC, was previously isolated and characterized and was shown to be induced 3- to 5-fold by exposure to ethanol. In the present study, antibody against rabbit P-450ALC was used to identify a homologous protein in alcohol dehydrogenase-negative (ADH-) and -positive (ADH+) deermice, Peromyscus maniculatus. The antibody reacts with a single protein having an apparent molecular weight of 52,000 on immunoblots of hepatic microsomes from untreated and ethanol-treated deermice from both strains. The level of the homologous protein was about 2-fold greater in microsomes from naive ADH- than from naive ADH+ animals. Ethanol treatment induced the protein about 3-fold in the ADH+ strain and about 4-fold in the ADH- strain. The antibody to rabbit P-450ALC inhibited the microsomal metabolism of ethanol and aniline. The homologous protein, termed deermouse P-450ALC, catalyzed from 70 to 80% of the oxidation of ethanol and about 90% of the hydroxylation of aniline by microsomes from both strains after ethanol treatment. The antibody-inhibited portion of the microsomal activities, which are attributable to the P-450ALC homolog, increased about 3-fold upon ethanol treatment in the ADH+ strain and about 4-fold in the ADH- strain, in excellent agreement with the results from immunoblots. The total microsomal P-450 content and the rate of ethanol oxidation were induced 1.4-fold and 2.2-fold, respectively, by ethanol in the ADH+ strain and 1.9-fold and 3.3-fold, respectively, in the ADH- strain. Thus, the total microsomal P-450 content and ethanol oxidation underestimate the induction of the P-450ALC homolog in both strains. A comparison of the rates of microsomal ethanol oxidation in vitro with rates of ethanol elimination in vivo indicates that deermouse P-450ALC could account optimally for 3 and 8% of total ethanol elimination in naive ADH+ and ADH- strains, respectively. After chronic ethanol treatment, P-450ALC could account maximally for 8% of the total ethanol elimination in the ADH+ strain and 22% in the ADH- strain. Further, cytochrome P-450ALC appears to be responsible for about one-half of the increase in the rate of ethanol elimination in vivo after chronic treatment with ethanol. These results indicate that the contribution of P-450ALC to ethanol oxidation in the deermouse is relatively small. Desferrioxamine had no effect on rates of ethanol uptake by perfused livers from ADH-negative deermice, indicating that ethanol oxidation by a hydroxyl radical-mediated mechanism was not involved in ethanol metabolism in this mutant.(ABSTRACT TRUNCATED AT 400 WORDS)     

Alveoli increase in number but not size from birth to adulthood in rhesus monkeys

Postnatal developmental stages of lung parenchyma in rhesus monkeys is about one-third that of humans. Alveoli in humans are reported to be formed up to 8 yr of age. We used design-based stereological methods to estimate the number of alveoli (N(alv)) in male and female rhesus monkeys over the first 7 yr of life. Twenty-six rhesus monkeys (13 males ranging in age from 4 to 1,920 days and lung volumes from 41.7 to 602 cm(3), 13 females ranging in age from 22 to 2,675 days and lung volumes from 43.5 to 380 cm(3)) were necropsied and lungs fixed, isotropically oriented, fractionated, sampled, embedded, and sectioned for alveolar counting. Parenchymal, alveolar, alveolar duct core air, and interalveolar septal tissue volumes increased rapidly during the first 2 yr with slowed growth from 2 to 7 yr. The rate of change was greater in males than females. N(alv) also showed consistent growth throughout the study, with increases in N(alv) best predicted by increases in lung volume. However, mean alveolar volume showed little relationship with age, lung volume, or body weight but was larger in females and showed a greater size distribution than in males. Alveoli increase in number but not volume throughout postnatal development in rhesus monkeys.     

Mechanism of the alcohol cyclic pattern: role of the hypothalamic-pituitary-thyroid axis

The cause of the cycle of urinary alcohol levels (UALs) in rats fed ethanol continually at a fixed rate is unknown. Rats were fed ethanol intragastrically at a constant dose for 2 mo, and daily body temperatures and UALs were recorded. Body temperature cycled inversely to UAL, suggesting that the rate of metabolism could be mechanistically involved in the rate of ethanol elimination during the cycle. To document this, whole body O(2) consumption rate was monitored daily during the cycle. The rate of O(2) consumption correlated positively with the change in body temperature and negatively with the change in UAL. Since the metabolic rate responds to changes in body temperature, thyroid hormone levels were measured during the UAL cycle. T(4) levels correlated positively with the O(2) consumption rate and negatively with the UALs. In a second experiment using propylthiouracil treatment, UALs did not cycle and a fall in body temperature failed to stimulate an increase in the rate of ethanol elimination. Consequently, rats died of overdose. Likewise, in a third experiment using rats with severed pituitary stalks, UALs failed to cycle and rats died of overdose. From these observations it was concluded that the UAL cycle depends on an intact hypothalamic-pituitary-thyroid axis response to the ethanol-induced drop in body temperature by increasing the rate of ethanol elimination.     

Reaction times for hand movements made in response to visual versus vibratory cues

Reaction times were determined for monkeys and humans who made wrist flexion and extension movements in response to vibratory and visual cues. Humans initiated movements approximately 50 msec sooner in response to vibratory as compared to visual cues. For monkeys, this difference was approximately 100 msec. Mean daily reaction times for monkeys and humans improved with practice until they reached a steady level of performance. Increased differences between vibratory and visual reaction times were weakly correlated with increased age of humans. The increase in the differences appeared to result from decreased reaction times by older subjects for vibratory-cued movements; reaction times for visually cued movements did not consistently vary across the age range of subjects tested (19-36 years). The results obtained using this novel paradigm suggest that it may be a useful tool for simultaneously testing behavioral performance or neurological function during somatosensorimotor and visuomotor tasks.     

Quantification and kinetics of purine catabolism in Dalmatian dogs at low and high purine intakes

1. In eight Dalmatian dogs low and high purine intakes resulted in plasma urate levels from 25 to 185 mumol/l. 2. The relationship between purine intake and excretion of uric acid and allantoin per day was described by linear regression equations. 3. The elimination of endogenous purines was 1.8 mmol/day for urate and 1.7 mmol/day for allantoin. Exogenous purines increased renal excretion by 0.57 mmol/mmol. 4. Kinetic measurements with [2(-14)C]uric acid infused continuously into each of two dogs on low and high purine revealed increases of plasma pool (urate + allantoin) of 3.3 fold and entry rate of 4.0 fold. Conversion of urate into allantoin increased from 20 to 36%. 5. Renal elimination of catabolites increased 3.3 fold and exhalation rate of purine-CO2 379 fold. Extra-renal elimination at high purine intake was quantitatively similar to humans and closely related to pool size.     

Reaction Times for Hand Movements Made in Response to Visual versus Vibratory Cues

Reaction times were determined for monkeys and humans who made wrist flexion and extension movements in response to vibratory and visual cues. Humans initiated movements approximately 50 msec sooner in response to vibratory as compared to visual cues. For monkeys, this difference was approximately 100 msec. Mean daily reaction times for monkeys and humans improved with practice until they reached a steady level of performance. Increased differences between vibratory and visual reaction times were weakly correlated with increased age of humans. The increase in the differences appeared to result from decreased reaction times by older subjects for vibratory-cued movements; reaction times for visually cued movements did not consistently vary across the age range of subjects tested (19-36 years). The results obtained using this novel paradigm suggest that it may be a useful tool for simultaneously testing behavioral performance or neurological function during somatosensorimotor and visuomotor tasks.     

Osmotic fragility of erythrocytes in Bolivian and Brazilian squirrel monkeys (Saimiri sciureus).

Median corpuscular fragility of erythrocytes does not differ significantly between fed and fasted Bolivian and Brazilian squirrel monkeys and are similar to values reported in humans and rhesus monkeys. This report further confirms that the fasting hyperbilirubinemia present only in Bolivian squirrel monkeys with a Gilbert-like syndrome is not due to an increased fragility of erythrocytes and should be classified as a nonhemolytic hyperbilirubinemia.     

Ethanol Affects the Development of Sensory Hair Cells in Larval Zebrafish (Danio rerio)

Children born to mothers with substantial alcohol consumption during pregnancy can present a number of morphological, cognitive, and sensory abnormalities, including hearing deficits, collectively known as fetal alcohol syndrome (FAS). The goal of this study was to determine if the zebrafish lateral line could be used to study sensory hair cell abnormalities caused by exposure to ethanol during embryogenesis. Some lateral line sensory hair cells are present at 2 days post-fertilization (dpf) and are functional by 5 dpf. Zebrafish embryos were raised in fish water supplemented with varying concentrations of ethanol (0.75%–1.75% by volume) from 2 dpf through 5 dpf. Ethanol treatment during development resulted in many physical abnormalities characteristic of FAS in humans. Also, the number of sensory hair cells decreased as the concentration of ethanol increased in a dose-dependent manner. The dye FM 1-43FX was used to detect the presence of functional mechanotransduction channels. The percentage of FM 1-43-labeled hair cells decreased as the concentration of ethanol increased. Methanol treatment did not affect the development of hair cells. The cell cycle markers proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU) demonstrated that ethanol reduced the number of sensory hair cells, as a consequence of decreased cellular proliferation. There was also a significant increase in the rate of apoptosis, as determined by TUNEL-labeling, in neuromasts following ethanol treatment during larval development. Therefore, zebrafish are a useful animal model to study the effects of hair cell developmental disorders associated with FAS.     

Caudate electrochemical response following amphetamine administration in pigtail monkeys

In vivo electrochemical and heart rate (HR) recordings following amphetamine (AMPH) (0.8 mg/kg) and saline administration were made from caudate in four young adult pigtail (M. nemestrina) monkeys using linear sweep voltammetry. One hour following drug injection, two familiar humans served as test stimuli, and were visually exposed to the animals for 15-minute epochs each. One was threatening to the animals, and one was not. AMPH produced a significant increase in height of the electrochemical peak thought to represent oxidation of dopamine and its metabolites. Heart rate (HR) decreased during the time the peak height was increasing. HR and peak height increased during presentation of both humans under both AMPH and saline conditions. However, peak height increase under AMPH, but not saline, conditions discriminated the negative from neutral stimulus. The findings demonstrate that AMPH administration induces a significant increase in the height of a major electroactive peak in the caudate nucleus of pigtail monkeys, and further that such amphetamine-induced increases can be manipulated by altering the affective and/or emotional state of the animal.     

Perception of shape-from-motion in macaque monkeys and humans

Motion is one of the most efficient cues for shape perception. We conducted behavioral experiments to examine how monkeys perceive shapes defined by motion cues and whether they perceive them as humans do. We trained monkeys to perform a shape discrimination task in which shapes were defined by the motion of random dots. Effects of dot density and dot speed on the shape perception of monkeys were examined. Human subjects were also tested using the same paradigm and the test results were compared with those of monkeys. In both monkeys and humans, correct performance rates declined when density or speed of random dots was reduced. Both of them tended to confuse the same combinations of shapes frequently. These results suggest that monkeys and humans perceive shapes defined by motion cues in a similar manner and probably have common neural mechanisms to perceive them. Electronic Publication     

Peripheral aromatization: studies on controlling factors

Using constant infusions of 3H-labeled androgens and 14C-labeled estrogens with measurements of radiolabeled estrogens in blood and/or urine we have carried out studies on the peripheral aromatization of androgens in humans, nonhuman primates, sheep, and rabbits. In the human, aromatization is increased in women as they become postmenopausal, although the mechanism remains uncertain. In humans and cynomolgus monkeys the administration of ACTH and/or glucocorticoids does not increase peripheral aromatization, but results in a slight decrease in the aromatization of androstenedione. The administration of l-thyroxine to cynomolgus monkeys increases peripheral aromatization of androstenedione from basal, 1.16 +/- 0.15%, to 1.71 +/- 0.14% probably due to increased tissue blood flow. The aromatization of testosterone is not affected, probably due to an increase in sex hormone-binding globulin. Peripheral aromatization occurs to a similar degree in humans, rhesus and cynomolgus monkeys, and baboons, but is much lower in sheep and rabbits. The compound 10-(2-propynyl)-estr-4-ene-3,17-dione is an effective inhibitor of the peripheral aromatization of both androstenedione and testosterone.