Ethanol elimination in males and females: relationship to menstrual cycle and body composition

Ethanol pharmacokinetics were determined following oral ethanol, 0.5 gm per kg, in nine normal women and 10 normal men, and related to total body water measured by 3H-water dilution and body fat determined anthropometrically. Ethanol pharmacokinetics were similar in the females throughout the menstrual cycle. No variation was seen in mean peak blood ethanol concentration or elimination rate in the midfollicular (Days 8 to 10) and midluteal (Days 22 to 24) phases. Mean peak blood ethanol values were significantly higher in females (88 +/- 3 mg per 100 ml) than in males (75 +/- 4 mg per 100 ml) (p less than 0.05), and the mean area under the ethanol concentration-time curve was significantly greater in females (241 +/- 12 mg X hr per 100 ml) than in males (177 +/- 11 mg X hr per 100 ml) (p less than 0.001). There was no significant sex difference in mean ethanol elimination rates. The mean apparent volume of distribution of ethanol in female (0.59 +/- 0.02 liter per kg) was less than in males (0.73 +/- 0.02 liter per kg) (p less than 0.001). Both apparent volume of distribution of ethanol and area under curve were significantly correlated with total body water suggesting that the sex differences in ethanol pharmacokinetics were due to sex differences in body water content. The sex differences in ethanol pharmacokinetics may partly explain reports of male-female differences in the natural history of certain ethanol-related disorders.     

Hepatic thyroid hormone levels following chronic alcohol consumption: direct experimental evidence in rats against the existence of a hyperthyroid hepatic state

To study the effect of chronic alcohol consumption on hepatic levels of thyroid hormones, female Sprague-Dawley rats (n = 24) were pair-fed nutritionally adequate liquid diets containing either ethanol (36% of total calories) or isocaloric carbohydrates for 21 days. Compared to controls, chronic alcohol consumption failed to result in a significant change of hepatic thyroid hormone levels (thyroxine: 14.7 +/- 1.81 ng per gm of liver wet weight vs. 15.0 +/- 1.59; triiodothyronine: 2.60 +/- 0.16 ng per gm of liver wet weight vs. 2.66 +/- 0.18). Similar results were obtained when the hepatic levels of thyroid hormones were expressed per total liver, per gram of liver protein or per 100 gm of body weight. Moreover, prolonged alcohol ingestion led to a significant reduction of serum total thyroxine by 31.6% (p less than 0.001), free thyroxine by 38.9% (p less than 0.02), total triiodothyronine by 40.2% (p less than 0.001) and free triiodothyronine by 56.1% (p less than 0.001) when compared to their pair-fed controls, whereas thyroid-stimulating hormone levels remained virtually unchanged. These data, therefore, clearly show that chronic alcohol consumption is incapable of creating a hyperthyroid hepatic state in rats, and limit the rationale for antithyroid treatment in patients with alcoholic liver disease.     

Fatty acid-binding protein: a major contributor to the ethanol-induced increase in liver cytosolic proteins in the rat

To study the acute and chronic effects of ethanol on hepatic fatty acid-binding protein, rats were pair-fed with liquid diets containing 36% of energy either as ethanol or as additional carbohydrate for 4 to 5 weeks. Animals were killed 90 min after intragastric administration of diets with or without ethanol. Alcohol feeding markedly increased liver triglycerides, with a modest rise in nonesterified fatty acids. Alcohol-fed rats developed hepatomegaly, with a 48% increase in hepatic cytosolic proteins. Fatty acid binding was first assessed by the kinetics of [14C]palmitate binding to cytosolic proteins. The maximal binding capacity more than doubled in the cytosol of the ethanol-fed rats compared to pair-fed controls, whereas the dissociation constant increased by 64%. Acute ethanol administration (3 gm per kg body weight) either to ethanol-fed or control rats did not have a significant effect. To identify the fatty acid-binding protein, labeled cytosolic proteins were fractionated by gel filtration: most of the cytosolic fatty acids eluted as a single peak in the 12,000 to 18,000 molecular weight region corresponding to the hepatic fatty acid-binding protein. The increase in this protein, confirmed by radial immunodiffusion (27.0 +/- 1.4 mg per 100 gm body weight vs. 11.2 +/- 1.6, in controls; p less than 0.01), accounted for 22% of the total rise in cytosolic protein induced by chronic ethanol feeding.     

Transferrin metabolism in alcoholic liver disease

The metabolism of transferrin was studied using purified 125I-labeled transferrin in 11 alcoholic patients; six with fatty liver and five with cirrhosis. Six healthy subjects whose alcohol intake was les than 40 gm daily were studied as a control group. There were no significant differences in the mean fractional catabolic rate and plasma volume in the alcoholic groups when compared with control subjects. A significantly decreased mean serum transferrin concentration was found in the alcoholic cirrhotic patients (1.8 +/- 0.3 gm per liter vs. 2.9 +/- 0.2; p less than 0.01), resulting from diminished total body synthesis (0.9 +/- 0.2 mg per kg per hr vs. 1.8 +/- 0.2; p less than 0.01). In contrast, in the patients with alcoholic fatty liver, the mean total body transferrin synthesis (2.4 +/- 0.3 mg per kg per hr) was significantly increased when compared with controls (p less than 0.05). For all the alcoholic patients, the serum transferrin correlated with transferrin synthesis (r = + 0.70; p less than 0.01) but the serum iron did not. These results suggest that, in alcoholic cirrhosis, transferrin synthesis is decreased, probably reflecting diminished synthetic capacity by the liver. In contrast, in patients with alcoholic fatty liver, transferrin turnover is accelerated.     

Effect of ethanol on splanchnic hemodynamics in awake and unrestrained rats with portal hypertension

Alcoholic liver disease is frequently accompanied by portal hypertension. We have previously shown that alcohol intake in awake, unrestrained rats is followed by an increase in portal tributary blood flow. In this study, the effect of ethanol on splanchnic hemodynamics in rats with portal hypertension was analyzed. Portal hypertension was induced by partial ligation of the portal vein. This procedure resulted in an increase in portal tributary and hepatic arterial blood flows compared to sham-operated animals. Ethanol (2 gm per kg, oral) increased portal tributary blood flow in both sham-operated and portal vein-ligated rats (sham + water = 37.6 +/- 1.4; sham + ethanol = 63.1 +/- 1.9; p less than 0.01; partial portal vein stenosis + water = 53.2 +/- 3.3; partial portal vein stenosis + ethanol = 69.5 +/- 2.2 ml.kg-1.min-1; p less than 0.01). In sham-operated rats, hepatic artery blood flow was unchanged following ethanol (sham + water = 6.6 +/- 0.7; sham + ethanol = 7.1 +/- 1.0 ml.kg-1.min-1), whereas in portal vein-ligated rats, flow was increased (partial portal vein stenosis + water = 13.7 +/- 1.4; partial portal vein stenosis + ethanol = 19.8 +/- 1.1 ml.kg-1.min-1; p less than 0.025). The adenosine receptor blocker 8-phenyltheophylline suppressed only the ethanol-induced increase in both portal tributary and hepatic artery blood flows in portal vein-ligated rats. The increases in hepatic artery and portal tributary blood flows observed in portal vein-ligated rats without ethanol were not influenced by 8-phenyltheophylline.(ABSTRACT TRUNCATED AT 250 WORDS)     

S-adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon

Chronic ethanol consumption by baboons (50% of energy from a liquid diet) for 18 to 36 mo resulted in significant depletion of hepatic S-adenosyl-L-methionine concentration: 74.6 +/- 2.4 nmol/gm vs. 108.9 +/- 8.2 nmol/gm liver in controls (p less than 0.005). The depletion was corrected with S-adenosyl-L-methionine (0.4 mg/kcal) administration (102.1 +/- 15.4 nmol/gm after S-adenosyl-L-methionine-ethanol, with 121.4 +/- 11.9 nmol/gm in controls). Ethanol also induced a depletion of glutathione (2.63 +/- 0.13 mumol/gm after ethanol vs. 4.87 +/- 0.36 mumol/gm in controls) that was attenuated by S-adenosyl-L-methionine (3.89 +/- 0.51 mumol/gm in S-adenosyl-L-methionine-methanol vs. 5.22 +/- 0.53 mumol/gm in S-adenosyl-L-methionine controls). There was a significant correlation between hepatic S-adenosyl-L-methionine and glutathione level (r = 0.497; p less than 0.01). After the baboons received ethanol, we observed the expected increase in circulating levels of the mitochondrial enzyme glutamic dehydrogenase: 95.1 +/- 21.4 IU/L vs. 13.4 +/- 1.8 IU/L; p less than 0.001, whereas in a corresponding group of animals given S-adenosyl-L-methionine with ethanol, the values were only 30.3 +/- 7.1 IU/L (vs. 9.6 +/- 0.7 IU/L in the S-adenosyl-L-methionine controls). This attenuation by S-adenosyl-L-methionine of the ethanol-induced increase in plasma glutamic dehydrogenase (p less than 0.005) was associated with a decrease in the number of giant mitochondria (assessed in percutaneous liver biopsy specimens), with a corresponding change in the activity of succinate dehydrogenase, a mitochondrial marker enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)     

Possible role of acetaldehyde in ethanol-related rectal cocarcinogenesis in the rat

Prospective epidemiologic studies have reported an increased risk of rectal cancer following chronic ethanol ingestion. The effect of ethanol on chemically induced colorectal carcinogenesis is controversial depending on the experimental conditions. In the present study the effect of chronic ethanol administration on acetoxymethylmethylnitrosamine-induced rectal cancer and the possible role of acetaldehyde in this process were investigated. Chronic ethanol administration resulted in an earlier occurrence of rectal tumors in this animal model. Because the concomitant administration of cyanamide, a potent acetaldehyde dehydrogenase inhibitor, showed a positive trend toward increased incidences of tumors, acetaldehyde could be involved in the ethanol-associated carcinogenesis. To measure colonic acetaldehyde, 12 chronically ethanol-fed and control rats received an acute dose of ethanol (2.5 g/kg body wt). The mucosal concentration of acetaldehyde was significantly higher in the rectum compared with the cecum (198 +/- 23 vs. 120 +/- 23 nmoles.g colon-1, p less than 0.05), but was not affected by chronic ethanol feeding. Furthermore, 6 germ-free rats had significantly lower acetaldehyde concentrations in the rectum (84 +/- 11 vs. 234 +/- 33 nmoles.g colon-1, p less than 0.01) and in the cecum (59 +/- 13 vs. 121 +/- 33 nmoles.g colon-1, p less than 0.05) compared with 6 conventional animals, and this was paralleled by the number of fecal bacteria in the 2 intestinal segments. In addition, to determine the effect of chronic ethanol feeding on colorectal cell turnover, 30 animals were pair-fed liquid diets. Using the metaphase-arrest technique, alcohol feeding induced rectal (19.1 +/- 2.0 vs. 9.1 +/- 1.8 cells.crypt-1.h-1, p less than 0.01), but not cecal (18.9 +/- 1.3 vs. 22.2 +/- 3.3 cells.crypt-1.h-1, p greater than 0.05) hyperregeneration. This was accompanied by an increase in the crypt proliferative compartment and increased mucosal ornithine decarboxylase activity (63 +/- 18 vs. 22 +/- 6 pmoles.hr-1.mg protein-1, p less than 0.05). The data show that chronic ethanol ingestion accelerates chemically induced rectal carcinogenesis and raise the possibility that acetaldehyde probably generated through bacterial ethanol oxidation may be involved in this process. The secondary hyperregeneration of the mucosa, observed after alcohol feeding, could by itself favour carcinogenesis.     

Benfluorex and blood glucose control in non insulin-dependent diabetic patients

Benfluorex has been reported to decrease blood glucose in different dismetabolic conditions, particularly in noninsulin-dependent diabetic (NIDD) patients, but the mechanism of this effect is poorly known. We evaluate fasting glucose production (3H-glucose infusion) and B-cell secretion (phi 1, phi 2 and glucose utilization SI) (minimal model technique) in 7 mild, diet treated, NIDDM patients after 6-week administration of benfluorex (450 mg/day) and placebo, in random sequence and double blind design. Body weight, HbA1c, plasma glucose profile, fasting plasma insulin, lactate, pyruvate, beta-OH-butyrate, total cholesterol, HDL-cholesterol and triglycerides were also measured at the end of each treatment. Mean values of body weight (71 +/- 4 vs 69 +/- 4 kg, p less than 0.01), HbA1c (8.3 +/- 0.2 vs 7.7 +/- 0.2%, p less than 0.01), fasting plasma glucose (137.0 +/- 6.5 vs 121.4 +/- 5.6 mg/dl, p less than 0.01), lactate (1.82 +/- 0.13 vs 1.22 +/- 0.11 mmol/l, p less than 0.0025) pyruvate (0.164 +/- 0.011 vs 0.095 +/- 0.010 mmol/l, p less than 0.0005), and beta-OH-butyrate (0.91 +/- 0.06 vs 0.66 +/- 0.04 mmol/l, p less than 0.005) were significantly lower after benfluorex than after placebo. phi 1, phi 2 and SI values were not significantly different in the two treatments. Fasting glucose production was significantly lower after benfluorex than after placebo: 2.46 +/- 1.57 vs 1.84 +/- 0.85 mg/kg.min, p less than 0.02. These results demonstrate that 6-week treatment with benfluorex produces a significant blood glucose lowering effect in mild NIDDM patients, mainly by decreasing glucose production.     

H2-receptor antagonists and hepatic drug disposition

The effect of four H2-receptor antagonists (cimetidine, burimamide, oxmetidine, and ranitidine) on antipyrine elimination was studied in the isolated perfused rat liver. The first three drugs are substituted imidazoles, whereas ranitidine contains a furanyl nucleus. Isolated livers were perfused using a 100-ml, recycling, constant flow circuit for 4 hr. Antipyrine elimination was studied with or without an H2-receptor antagonist present. In all experiments, antipyrine concentrations declined monoexponentially. In control experiments (no other drug present), antipyrine clearance was 32.5 +/- 0.9 ml per hr. This was greatly reduced in the presence of cimetidine (clearance = 10.1 +/- 0.8 and 5.8 +/- 1.5 ml per hr after 1 and 5 mg doses, p less than 0.01) and burimamide (4.5 +/- 0.6 and 3.0 +/- 1.7 ml per hr, p less than 0.001). By contrast, neither oxmetidine nor ranitidine significantly altered antipyrine pharmacokinetics. These results indicate that the inhibitory effect on hepatic mixed-function oxidases is rapid in onset, independent of H2-receptor antagonist activity, and is not an inevitable consequence of the presence of an imidazole nucleus.     

Interaction of ethanol with beta-carotene: delayed blood clearance and enhanced hepatotoxicity.

Because we had found that ethanol interacts with retinol, we investigated whether it also affects its precursor, beta-carotene. In 14 baboons fed ethanol (50% of total energy) for 2 to 5 yr with a standard amount of beta-carotene (one 200-gm carrot/day), levels of beta-carotene were much higher than in controls fed isocaloric carbohydrate, both in plasma (122.5 +/- 30.9 nmol/dl vs. 6.3 +/- 1.4 nmol/dl; p less than 0.005) and in liver (7.9 +/- 1.1 nmol/gm vs. 1.8 +/- 0.5 nmol/gm; p less than 0.001). Even 20 days after withdrawal of the carrots, plasma beta-carotene levels remained higher in alcohol-fed baboons than in controls (10.1 +/- 3.8 nmol/dl vs. less than 0.1 nmol/dl). Next, the diet was supplemented with beta-carotene beadlets: in four pairs of baboons given a low dose of beta-carotene (3 mg/1,000 kcal), plasma levels were significantly higher in alcohol-fed animals than in controls, even when expressed per cholesterol (although the latter increased with alcohol intake). Seven pairs of animals were given a higher dose (30 mg/1,000 kcal) of beta-carotene for 1 mo, followed, in four pairs, by 45 mg for another month. On cessation of beta-carotene treatment, plasma levels decreased more slowly in the alcohol-fed baboons than in the controls. Percutaneous liver biopsy specimens revealed that liver concentrations of beta-carotene correlated with plasma levels but were higher in the alcohol-fed baboons than in the control baboons, whereas the beta-carotene-induced increase in liver retinoids was lower (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Oral N-acetylcysteine reduces bleomycin-induced collagen deposition in the lungs of mice.

N-acetylcysteine (NAC) has been employed in the treatment of acute lung injury but its therapeutic value is as yet unproven. In the present study we examined the effect of both L- and D-forms of NAC as inhibitors of bleomycin-induced fibrosis in mice. We hypothesized that, because of the D-form is not metabolized, it may be more effective than the L-form in ameliorating lung injury and fibrosis. Both drugs were given daily in the drinking water at a dose of approximately 400 mg.kg-1 body weight commencing one week prior to a single intratracheal instillation of bleomycin at a dose of 6 mg.kg-1 body weight. Lung injury was assessed 35 days later by measuring total lung collagen content, lung wet weight and examination of tissues by light and electron microscopy. Total collagen content and lung wet weight of animals receiving bleomycin together with L-NAC were 2.90 +/- 0.03 mg and 0.23 +/- 0.01 g, respectively. The values for collagen content, but not wet weight, were significantly less (p less than 0.05) than those given for bleomycin alone (3.90 +/- 0.02 mg and 0.260 +/- 0.005 g, respectively), but greater than (p less than 0.05) controls (2.10 +/- 0.01 mg and 0.160 +/- 0.002 g, respectively). Values for collagen content and wet weight of animals given bleomycin together with D-NAC (3.10 +/- 0.02 mg and 0.21 +/- 0.01 mg, respectively) were both significantly greater than values for control animals but lower than animals given bleomycin alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of growth hormone on weight gain and pulmonary function in patients with chronic obstructive lung disease

Thirty to 60 percent of patients with chronic obstructive pulmonary disease (COPD) are malnourished, and this affects ventilatory muscle function and prognosis for survival adversely. We studied the effect of growth hormone (GH) in malnourished patients with COPD (n = 7, mean FEV1 of 1.1 +/- 0.2 L, 45 +/- 7 percent of predicted values; less than 90 percent of ideal body weight). The subjects received a balanced diet of 35 kcal/kg with 1 g of protein/kg for 1 week (pre-GH). During the following three weeks, they received the same diet plus subcutaneous injections of recombinant methionyl human GH (0.05 mg/kg daily). The subjects had no significant weight gain during the week of diet alone (0.07 +/- 0.11 kg, p = NS) but they had substantial weight gain during the first week of GH treatment (1.37 +/- 0.23 kg, p less than 0.01). Nitrogen balance also improved during GH treatment (+1.6 +/- 0.7 g/day on diet alone vs +3.8 +/- 0.5 g/day on diet plus GH, p less than 0.02). Maximal inspiratory pressure improved by 27 +/- 8 percent after GH treatment (p less than 0.02). No significant adverse effects occurred. Further study of the potential usefulness of GH in COPD utilizing a placebo-controlled trial is warranted.     

Effect of aging on in vivo and in vitro ethanol metabolism and its toxicity in F344 rats

To investigate the effect of aging on ethanol metabolism, 24 male and female F344 rats aged 2 and 12 mo that were fed a laboratory diet received ethanol (1.2 and 2.5 g/kg body wt) intraperitoneally. In male rats, in vivo ethanol elimination significantly decreased according to age both at high (436 +/- 38 vs. 294 +/- 27 mg/kg.h; p less than 0.01) and low (365 +/- 19 vs. 261 +/- 8 mg/kg.h; p less than 0.01) blood ethanol concentrations. Age did not influence the specific activity of hepatic or gastric alcohol dehydrogenase, whereas the activity was significantly decreased with age in the liver (p less than 0.05) and in the stomach (p less than 0.001) when related to body weight. In addition, the activity of the hepatic microsomal ethanol oxidizing system decreased significantly according to age (8.7 +/- 0.5 vs. 6.00 +/- 0.3 nmol/min.mg micr. protein; p less than 0.001). To study the response of ethanol-metabolizing enzymes to chronic ethanol ingestion, 2- and 19-mo-old male F344 rats were pair-fed nutritionally adequate liquid diets containing 36% of total calories either as ethanol or isocaloric carbohydrate for 3 wk. In this experiment specific alcohol dehydrogenase activity was not significantly affected by age, whereas the hepatic microsomal function estimated by the determination of cytochrome P450, microsomal ethanol oxidizing system, and aniline hydroxylation as well as hepatic mitochondrial low Km-acetaldehyde dehydrogenase activity was found to be markedly depressed with age (p less than 0.01). Chronic ethanol consumption increased microsomal enzyme activities in older rats to levels comparable to those observed in young animals prior to ethanol administration. Chronic ethanol feeding also resulted in an increased hepatic fat accumulation, which was significantly enhanced in older rats. In contrast to male rats, in vivo ethanol metabolism was practically identical for 2- and 12-mo-old female rats. These data demonstrate an enhanced toxicity of alcohol in older compared to younger male but not female rats associated with a delay in alcohol elimination both at high and low ethanol blood concentrations and a decrease in ethanol- and acetaldehyde-metabolizing enzyme activities.     

Comparative effectiveness of ranitidine (150 mg X 2) and cimetidine (400 mg x 2) in the treatment of acute duodenal ulcer. A French multicenter controlled clinical trial

In a single-blind multicenter trial, 444 patients with duodenal ulcer (DU) proven by endoscopy were randomly assigned to treatment with either ranitidine, 150 mg, or cimetidine, 400 mg, morning and evening. Clinical assessments were carried out at 2 and 4 weeks and endoscopy at 4 weeks. The patients in the 2 groups were comparable. Cumulative healing rates at 4 weeks were 78.3 p. 100 in the ranitidine group (n = 226) and 65.6 p. 100 in the cimetidine group (n = 218) (p less than 0.003). Pain at the start was of similar severity in both groups, and disappeared at the same rate under ranitidine or cimetidine: 64 p. 100 patients were painless at 1 week, 80 p. 100 at 2 weeks and 88 p. 100 at 4 weeks. Thirty-eight patients complained of mild side effects: 22 on ranitidine (2 trial withdrawals) and 16 on cimetidine (1 trial withdrawal). Multifactorial analysis (logistic model) revealed that linear ulcers had a lower healing probability than round ulcers (p less than 0.002) whatever the treatment group (cimetidine: 47 p. 100 vs 68 p. 100, ranitidine 57 p. 100 vs 80 p. 100 respectively). Smoking habits (p less than 0.057) and age less than 40 years (p = 0.056) did not significantly influence healing rates, although smokers and younger patients under cimetidine had the lowest healing rate. Thus, at the dosage used in our trial, ranitidine is more efficient for healing DU at 4 weeks than cimetidine but not for pain relief.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired glucose tolerance in obesity is associated with insensitivity to insulin in multiple aspects of metabolism as assessed by a low dose incremental insulin infusion technique.

To determine whether Impaired Glucose Tolerance gives rise to additional defects in insulin action in lipid and ketone metabolism, thirty-two obese subjects were studied by low-dose incremental insulin infusion. Sixteen had Impaired Glucose Tolerance and 16 had normal glucose tolerance. Body mass index was 36.9-80.9 kg m-2 and was similar in each group. In patients with Impaired Glucose Tolerance, plasma insulin was higher in the fasted state (logarithmic mean 14.5 (9.8-21.6) (-SD(-)+SD) vs 9.6 (6.4-14.5) mU l-1, p less than 0.01) and during the infusion (p less than 0.001). The metabolic clearance rate for insulin at the highest infusion rate was lower (14.2 +/- 0.8 (+/- SE) vs 18.9 +/- 2.1 ml kg-1 min-1, p less than 0.05) in these subjects. Basal hepatic glucose production was higher in subjects with Impaired Glucose Tolerance (6.3 +/- 0.4 vs 4.5 +/- 0.6 mol kg-1 min-1, p less than 0.02) and remained elevated during infusion (p less than 0.01). Glucose disposal per unit circulating insulin at the maximal infusion rate was approximately half in subjects with Impaired Glucose Tolerance (0.022 +/- 0.010 vs 0.047 +/- 0.017 ml kg-1 min-1 mU-1 l, p less than 0.01). When simultaneous insulin and metabolite concentrations during the infusion are plotted as dose-response relationships, a difference in relative sensitivity to insulin in Impaired Glucose Tolerance over subjects with normal glucose tolerance is suggested for non-esterified fatty acids 0.72 (95% CI 0.62-0.84) and glycerol 1.85 (1.37-2.49).(ABSTRACT TRUNCATED AT 250 WORDS)     

Ethinylestradiol stimulates a biliary cholesterol-phospholipid cosecretion mechanism in the hamster

The mechanism of ethinylestradiol-induced biliary secretion of excess cholesterol, a potential causative factor of cholesterol gallstones, is not yet known. It might be related to altered bile acid metabolism, since the rate of cholesterol and phospholipid secreted into bile is thought to be influenced by the hydrophobicity of the bile acid species secreted. We therefore studied the effect of ethinylestradiol on bile acid metabolism and on secretory relationships between taurocholate and cholesterol/phospholipids in bile. Litter-matched Syrian female hamsters (80 to 100 gm body weight) were injected subcutaneously with either 0.2 ml per day corn oil (controls) or a pharmacologic dose of 5 mg per kg per day ethinylestradiol in corn oil (EE-hamsters; n = 6) for 5 days. On Day 6, bile was collected for 60 min (basal secretory rate) via a bile duct fistula after exclusion of the gallbladder. Then, a graded infusion of taurocholate was given for 110 to 130 min. Secretory rates (nmoles.min-1.-1 liver) for bile acids, cholesterol and phospholipids were determined and their mutual "linkage coefficients" (nmoles of secretory increment per 1 nmole of bile acid secreted) calculated by linear regression analysis. EE-hamsters had higher (p less than 0.02) basal secretory rates of cholesterol (0.71 +/- 0.21 vs. 0.45 +/- 0.10) and phospholipids (5.74 +/- 1.04 vs. 4.21 +/- 0.73) than controls at comparable bile flow and bile salt secretion rates. Cholic acid pool size and the fractional composition of bile acid species in bile were similar.(ABSTRACT TRUNCATED AT 250 WORDS)     

Liver triglyceride concentration and body protein metabolism in ethanol-treated rats: effect of energy and nutrient supplementation.

The objective of this study was to compare the metabolic effects of long-term ethanol consumption with oral (Lieber-DeCarli) and enteral feeding techniques. Enteral feeding allowed administration of greater amounts of energy and nutrients. After 21 days of treatment using the Lieber-DeCarli technique, the ethanol-treated rats had the following significant (P less than 0.05) differences from pair-fed controls: lower cumulative nitrogen balance (days 5-21; 2.8 +/- 0.1 g N vs. 3.5 +/- 0.1 g N), lower protein content of gastrocnemius muscle (289 +/- 17 mg vs. 358 +/- 11 mg) and intestinal mucosa (461 +/- 19 mg vs. 577 +/- 40 mg), higher plasma leucine concentration (147 +/- 8 mumol/L vs. 102 +/- 8 mumol/L), higher liver protein content (2222 +/- 122 mg vs. 1679 +/- 58 mg), and higher liver triglyceride concentration (38.4 +/- 2.8 mg/g vs. 8.7 +/- 1.0 mg/g). When rats received the same amount of nitrogen (1.5 g.kg-1.day-1) and ethanol (13 g.kg-1.day-1) but 16.3% more energy and nutrients by a surgically implanted gastric cannula (enterally fed), the effects of ethanol on nitrogen balance, tissue protein content, plasma leucine concentration, and liver triglyceride concentration were similar to those observed in the rats fed orally. It is concluded that the metabolic effects observed using the Lieber-DeCarli feeding technique are due to ethanol per se and not the synergism of ethanol and undernutrition as recently suggested.     

Marked impairment of the effect of hyperglycaemia on glucose uptake and glucose production in insulin-dependent diabetes

The effect of hyperglycaemia per se on glucose utilization and glucose production was evaluated in 12 patients with insulin-dependent diabetes and in 9 non-diabetic control subjects. In diabetic patients normoglycaemia was maintained during the night preceding the study by a variable intravenous insulin infusion. During the study endogenous insulin secretion was suppressed by somatostatin (300 micrograms h-1) and replaced by infusion of insulin (0.2 mU kg-1 min-1). Glucose utilization and hepatic glucose production rates were quantified at two plasma glucose concentrations (6.7 and 16.7 mmol l-1) using the two-step sequential hyperglycaemic clamp technique in combination with 3-3H-glucose tracer infusion. Duration of each step was 120 min. In diabetic patients glucose utilization, at a glucose concentration of 6.7 mmol l-1, was not different from normal (mean +/- SE: 2.9 +/- 0.2 vs 3.6 +/- 0.3 mg kg-1 min-1, 0.05 less than p less than 0.10), but the response to marked hyperglycaemia was significantly reduced (5.4 +/- 0.5 vs 9.4 +/- 1.0 mg kg-1 min-1, p less than 0.01). Hepatic glucose production was also normal at 6.7 mmol l-1 (1.4 +/- 0.1 vs 1.4 +/- 0.1 mg kg-1 min-1, NS), but whereas in control subjects glucose production was suppressed during hyperglycaemia of 16.7 mmol l-1 (0.3 +/- 0.4 mg kg-1 min-1, p less than 0.01), a slight increase was observed in diabetic patients (2.0 +/- 0.2 mg kg-1 min-1, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

More Rapid Elimination of Alcohol in Women as Compared to Their Male Siblings

Sex differences in rates of ethanol elimination were investigated in natural siblings to reduce genetic variability as compared to subjects chosen at random. Ethanol was infused intravenously in a dose of 0.6 g/kg of body weight over 45 to 60 min and serial blood samples obtained for 5 hr. The mean rate of ethanol elimination was higher in seven women, not different in one, and lower in one compared with their male siblings. The mean rate of ethanol elimination for all nine women was higher at 1.93 +/- 0.12 as compared with the value of 1.69 +/- 0.17 mmoles/kg body weight/hr in the men (p less than 0.05). Higher rates of ethanol metabolism in women as compared to men may be important in the increased susceptibility of women to liver injury caused by alcohol consumption.     

Lactulose reduces intracolonic acetaldehyde concentration and ethanol elimination rate in rats

BACKGROUND: Normal colonic bacteria possessing alcohol dehydrogenase activity can oxidize ethanol to acetaldehyde. Acetaldehyde recently has been shown to be a local carcinogen in humans. The aim of the study was to examine the effect of lactulose feeding on fecal and cecal pH, intracolonic acetaldehyde concentration, and total ethanol elimination rate in rats. METHODS: Sixty Wistar rats were divided into four groups. Groups 2 and 4 received lactulose daily (11 g/kg body weight for 14 days). On days 7 and 14, groups 1 and 2 received ethanol (1.5 g/kg body weight) intraperitoneally, whereas groups 3 and 4 received saline. RESULTS: Fecal and cecal pH values decreased significantly after lactulose treatment compared with the controls. Lactulose feeding reduced the total ethanol elimination rate by 13.8% (257 +/- 0.008 mg/kg/hr vs. 298 +/- 0.003 mg/kg/hr, p < 0.001) and the intracecal acetaldehyde concentration by 66.2% after ethanol (49 +/- 29 microM vs. 145 +/- 47 microM, p = 0.03) compared with the controls. CONCLUSION: Lactulose feeding to rats significantly reduces ethanol elimination rate and intraluminal acetaldehyde concentration in the colon after ethanol administration. This prebiotic thus could be used as an effective agent to block the microbial production of carcinogenic acetaldehyde in the large intestine.