Biomedical subjects
Publications and source records attributed to H K Seitz.
Chronic ethanol feeding together with the direct acting carcinogen AMMN led to an earlier occurrence of colorectal tumors in SD rats.
Hyperproliferation has been suggested to play a major role in bile acid-dependent colorectal tumor promotion. Effects of chronic feeding of chenodeoxycholic acid (CDC) and ursodeoxycholic acid (UDC) were tested on cell proliferation in the colon of male noninbred Wistar rats. By use of a dynamic method measuring actual rates of cell production, proliferation was modulated by both bile acids only in the proximal part of the colon. UDC feeding produced mild hyperproliferation of basal crypt cells (cell position 5-8: 7.6 +/- 2.0 vs. 3.5 +/- 1.3 cells/1,000 cells/hr--P less than .05; cell position 9-12: 18.1 +/- 10.7 vs. 10.3 +/- 2.9--P less than .05; cell position 13-16: 18.1 +/- 8.9 vs. 9.1 +/- 2.3--P less than .05). This finding reflected a characteristic compensatory response to superficial cell damage. However, CDC application did not effect cell regeneration in this crypt area but led to a striking drop of cell renewal in higher crypt cell positions (positions greater than or equal to 17), where no proliferation was detectable. These data suggest that CDC exerts its tumor-promoting effect by other means than hyperproliferation.
Since colchicine has been used in the treatment of alcoholic cirrhosis of the liver, the effect of this drug on ethanol metabolism in the rat has been investigated. The acute intraperitoneal injection of colchicine (500 micrograms per kg body weight) did not significantly influence in vivo ethanol elimination rate nor the ethanol peak blood concentrations following an acute dose of ethanol (3 g per kg body weight). Cytoplasmic hepatic alcohol dehydrogenase activity was not changed by in vitro colchicine. However, an approximate 30% inhibition of hepatic microsomal ethanol oxidation was observed by colchicine at a concentration of 4 microM and more. In addition, when colchicine was given chronically in a daily dose of 50 micrograms per kg body weight for 3 weeks, again in vivo ethanol disappearance from the blood was not affected by the drug. These data indicate that neither acute nor chronic colchicine administration alters in vivo ethanol elimination. But the question is raised whether colchicine can decrease hepatic acetaldehyde concentration following a therapeutic dose in vivo by inhibiting the hepatic ethanol metabolizing enzyme system. This could be a possible explanation for the observation that alcoholics improve their liver function under colchicine therapy although they continue to drink.
Chronic ethanol consumption in rats resulted in a striking fat accumulation in the acinar cells of the parotid gland demonstrated by light microscopy. In addition, a significant decrease in parotid wet weight (p greater than 0.02) and in protein content of the gland (p greater than 0.02) was observed following alcohol feeding. Wet weight, protein content, and morphology of the submaxillar gland were not affected by ethanol feeding. Alcohol metabolism, similar to that found in the pancreas, via a cytosolic alcohol dehydrogenase could be demonstrated in both the parotid and the submaxillar gland. However, the activity of this enzyme was not affected by chronic ethanol ingestion. Subsequently, chronic ethanol consumption significantly decreased salivary flow rate stimulated by pilocarpine hydrochloride (p greater than 0.02), salivary alpha-amylase activity (p greater than 0.02), and salivary sodium concentration (p greater than 0.01), whereas potassium concentration of the saliva was increased (p greater than 0.05). In contrast salivary total protein concentration was not affected by alcohol ingestion. The changes of salivary electrolyte composition observed after chronic ethanol feeding could be due to an altered aldosterone metabolism or to a change in aldosterone receptors of the parotid gland caused by ethanol administration. The reduced salivary flow could play a role in the pathogenesis of oropharyngeal cancer in the alcoholic.
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Cell proliferation was examined in the gastrointestinal tract of 30 pair fed rats having received an isocaloric liquid diet containing 36% of total calories either as ethanol or carbohydrates for four weeks. Utilising the metaphase arrest technique with vincristine, cell proliferation was measured as crypt cell production rate. This was selectively increased in the rectal mucosa of ethanol fed rats (19.1 +/- 2.0 vs 9.1 +/- 1.8 cells/crypt/h; p less than 0.005). There was a concomitant increase in proliferative compartment size (48.1 +/- 5.6% vs 30.1 +/- 8.5% of crypt population size; p less than 0.001). Serum gastrin concentrations were also found to be significantly increased after ethanol feeding (172 +/- 51 vs 106 +/- 27 pmol/l; p less than 0.01). The ethanol dependent proliferative changes in the rectal mucosa are predictive of higher susceptibility of this site to carcinogenesis, supporting experimental and epidemiological data. Increased gastrin concentrations may partly explain the observed rectal hyperproliferation. Other possible causes cannot, however, be excluded.
The oral administration of dietary chenodeoxycholic acid (1%), but not of ursodeoxycholic acid (1%), to male Sprague Dawley rats results in a significant increase in the colonic adenylate cyclase activity without any influence on the colonic cyclic-AMP phosphodiesterase activity. No effect of chronic bile acid feeding on the response of colonic adenylate cyclase to prostaglandin E2 and vasoactive intestinal peptide is observed. These data emphasize a dependence of the cyclic-AMP adenylate cyclase activation on the chemical structure of the bile acid. This may be of pathophysiologic relevance with respect to the frequently observed diarrhea as a side effect of oral chenodeoxycholic, but not ursodeoxycholic acid therapy for cholesterol gallstone dissolution in man.
Gamma-glutamyltransferase activity was determined in duodenal biopsies, and in the sera of forty-six non-alcoholic and eighteen alcoholic patients with a daily alcohol consumption of more than 80 g. Additionally, duodenal morphology was examined in biopsy material obtained at the same time. In both alcoholics (P less than 0.05) and in non-alcoholics (P less than 0.001) the duodenal gamma-glutamyltransferase activity revealed a significant positive correlation with duodenal villus length. In addition, alcoholics exhibited a significant decrease in duodenal villus length (338 +/- 13 vs. 363 +/- 13 microns, P less than 0.01), and a significant increase in duodenal gamma-glutamyltransferase activity (13.0 +/- 1.4 vs. 8.4 +/- 0.6 mU mg-1 protein, P less than 0.01) when compared to controls. No significant correlation was found between duodenal and serum gamma-glutamyltransferase activity in alcoholics and non-alcoholics. During follow up of two patients, duodenal gamma-glutamyltransferase activity decreased and duodenal villus length increased after withdrawing alcohol. These data underline the damaging effect of alcohol on the duodenal mucosa and demonstrate that chronic alcohol intake reversibly effects duodenal gamma-glutamyltransferase. In addition, the small intestine appears of minor importance as an origin for the elevated serum gamma-glutamyltransferase activities seen in the alcoholic.
In the second part of this review, the effect of ethanol on hepatic microsomal enzymes is primarily discussed. Since ethanol is metabolized via a cytochrome P-450 dependent biotransformation system (MEOS) in hepatic microsomes, the microsomal enzyme induction in the smooth endoplasmic reticulum has to be considered as an adaptive response. This enzyme induction results in an accelerated metabolism of ethanol. However, subsequently, the negative consequences of such a microsomal enzyme induction are predominant. Acetaldehyde production increases and oxygen consumption is enhanced leading to pericentral (perivenular) hypoxia. In addition, microsomal enzyme induction results in an enhanced metabolism of drugs, xenobiotics and hepatotoxins and thus to an increased production of toxic intermediates. Also procarcinogens are activated to a higher degree in microsomes following chronic ethanol consumption. Subsequently, an enhanced microsomal metabolism of vitamin A may explain the low serum concentrations of this vitamin in the alcoholic and may lead to toxic metabolites of retinol. The quantitative role of an enhanced reoxidation of NADH responsible for an increased oxidation of alcohol following chronic ethanol ingestion has still to be determined. However, according to recent investigations, a thyroid hormone induced hypermetabolism seems unlikely.
The interaction of ethanol with drugs and xenobiotics is complex because ethanol can affect any of the following steps; absorption, plasma protein binding, hepatic blood flow, distribution, hepatic uptake of drugs, and phase I and II hepatic metabolism. The ingestion of ethanol can lead to malabsorption of a variety of nutrients and can modify the absorption of various drugs. High concentrations of ethanol in conjunction with aspirin causes gastric mucosal damage. The principal effect of acute ethanol ingestion on drug metabolism is inhibition of microsomal drug metabolism. The synergistic effects of ethanol on central nervous system depressants can be explained by this mechanism. In contrast, chronic ethanol consumption increases mixed function oxidation and drug metabolism. The cross tolerance between ethanol and sedatives in chronic alcoholics may be due to this effect of alcohol. In addition, enhanced production of hepatotoxic products from certain drugs and xenobiotics and an increased activation of procarcinogens to carcinogens can result from this microsomal induction. The increased susceptibility to hepatotoxins and the enhanced carcinogenesis in the alcoholic may be explained by this fact. Other effects of the interaction between drugs and ethanol are the result of changes in organ susceptibility, best demonstrated for the central nervous system. Subsequently, the presence of liver disease has a great effect on drug metabolism in alcoholics.
The effect of chronic ethanol administration on 1, 2-dimethylhydrazine-induced rectal carcinogenesis was investigated in 32 paired male Sprague-Dawley rats fed a nutritionally-adequate liquid diet containing 36% of the total calories as either ethanol or isocaloric carbohydrates. Chronic ethanol ingestion increased the total number of rectal tumors significantly (17 vs 6; P less than 0.02), whereas no cocarcinogenic effect of ethanol was observed in other parts of the intestine. Alcohol did not influence tumor size or histopathology. A 47% increase in the activity of mucosal alcohol dehydrogenase in the distal colorectal region was found between chronically-ethanol-fed rats and pair-fed controls (0.241 +/- 0.019 vs 0.164 +/- 0.020 mumol/mg of protein/hr; P less than 0.01). This could in part explain the cocarcinogenic effect of alcohol in this tissue. Faecal bile acids, however, do not play a role as promotors of rectal carcinogenesis under the present experimental conditions. The results give experimental support to the epidemiologic findings of an increased incidence of rectal cancer in the alcoholic.
The incidence, distribution, size, and histopathology of grossly visible intestinal tumors induced by the parenteral administration of 1,2-dimethylhydrazine dihydrochloride were examined in 32 paired rats fed a nutritionally adequate liquid diet containing 36% of total calories either as ethanol or isocaloric carbohydrates. The liquid diets were begun 4 wk before the first of four weekly injections of 1,2-dimethylhydrazine dihydrochloride. At the time of the subcutaneous application of the procarcinogen, liquid diets were omitted for 3 wk, and were replaced by a standard laboratory diet. This feeding schedule was repeated four times, and after 32 wk the animals were killed. Chronic ethanol ingestion increased the total number of rectal tumors significantly (17 vs. 6, p less than 0.02). However, alcohol had no effect on tumor size or histopathology. Chronic ethanol ingestion did not exhibit any cocarcinogenic effect in tissues other than the rectum. A 47% increase in the activity of mucosal alcohol dehydrogenase in the distal colorectum was found between chronically ethanol-fed rats and pair-fed controls (0.241 +/- 0.019 vs. 0.164 +/- 0.020 mumol X mg protein-1 X h-1, p less than 0.01). This could in part explain the cocarcinogenic effect of alcohol in this tissue. Fecal bile acids, however, do not play a role as promoters of rectal cancer under the present experimental conditions. The data give experimental support to the epidemiologic findings of an increased incidence of rectal cancer in the alcoholic.
In western industrialized countries ethanol is an important etiologic factor in the development of cirrhosis of the liver. Metabolic, immunologic and physico-chemical alterations of the hepatocyte due to ethanol are involved in the pathogenesis of alcoholic liver disease. However, the mechanisms by which ethanol damages the liver are far from clear. During the last two decades, the effect of ethanol on multiple biochemical pathways of the hepatocyte has been investigated intensively. The present paper is focusing on the metabolic aspects of alcoholic liver disease. In the first part of the review, special emphasis has been led on the metabolites of ethanol oxidation, while in the second part microsomal enzyme induction due to alcohol has been discussed. More than 90% of ethanol metabolism takes place in the liver via cytoplasmic alcoholdehydrogenase (ADH) and via a microsomal ethanol oxidizing system (MEOS). The products of these reactions are reduced nicotinadenine dinucleotide phosphate (NADH), acetaldehyde and acetate. NADH alters the redox state of the liver cell favouring all reductive processes. This shift in metabolic pathways results in hyperlactacidaemia, lactacidosis, ketosis and hyperuricaemia. Disturbances of the carbohydrate metabolism may lead either to hypo- or hyperglycaemia. The altered redox state also influences the metabolic pathways of lipid metabolism leading to lipid accumulation within the hepatocyte which can be morphologically observed as alcoholic fatty liver. In addition, porphyrin and collagen metabolism is also affected by the increased NADH/NAD+ ratio. On the other hand, acetaldehyde damages the microtubular system and the mitochondria. Acetaldehyde may also be responsible for the increased lipidperoxidation after chronic ethanol ingestion.
A case report is given of a 46 year old person concerned professionally with melting gold, who exhibited bioptically and histologically verified lesions of the liver after chronic intoxication with cadmium. This patient was exposed throughout 8 years during his job activities to cadmium vapors. He exhibited during the time of investigation decreased renal function with tubular proteinuria as well as a polyneuropathy. In addition, hepatic lesions could be found, as small focal necrosis, fatty degeneration and fibrosis. Cadmium content of the liver was increased 13 times above normal.
We have assessed the effect of omeprazole (30 mg daily) on gastric acid secretion as well as on basal hormone levels (fasting gastrin; TSH, T3, T4, TBG; insulin, glucagon, C-peptide; prolactin, testosterone, 17-beta-oestradiol, dihydroepiandrosterone, cortisol and PTH) in 8 healthy volunteers before and after a 28 day treatment. On day 29, i. e. one day after the last omeprazole dose, mean stimulated acid output was still reduced from 27.4 +/- 3.5 mmol H+/h (+/- SEM) to 7.8 +/- 1.4 mmol H+/h (72% inhibition). Fasting gastrin levels were raised from 55.5 +/- 6.8 pg/ml to 80.9 +/- 6.7 pg/ml (33% increase). On day 39, stimulated gastric acid secretion and fasting gastrin levels have been returned to pretreatment values. Basal levels of prolactin, testosterone, TSH, T3, T4, TBG, cortisol, PTH, 17-beta-oestradiol, insulin, glucagon, c-peptide, dihydroepiandrosterone remained unchanged by a 28-day omeprazole treatment. Omeprazole is a highly effective antisecretory compound without any effect on the basal hormone levels tested. Even after 28 days its effect on acid secretion and fasting gastrin levels was fully reversible.
The effect of the substituted benzimidazole omeprazole on acid secretion after repeated administration to healthy volunteers has been studied. During repeated dosage of 30 mg once daily inhibition of basal and pentagastrin-stimulated acid output was increased from 30% after the first dose to about 60% after dose 4. The extent of inhibition did not further increase between day 5 and day 10. In four volunteers acid secretion returned to predose levels within 5 days after drug withdrawal. The 24-hour gastric acidity was reduced by about 72% and 82% after 9-day pretreatment with 30 mg and 60 mg omeprazole respectively. The antisecretory effect of omeprazole was independent of peak plasma concentrations. Omeprazole given once daily therefore possesses a long-lasting effect on gastric acid secretion, i.e. for more than 24 hours. This effect appears to be fully reversible since control levels of acid output are reached within 5 days.
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The colonic cyclic AMP system is known to be involved in intestinal secretion and can be stimulated by a variety of gastrointestinal hormones including prostaglandins. We have investigated the effect of chronic ethanol ingestion on the activity of the key enzymes in cyclic AMP metabolism--adenylate cyclase and cyclic AMP phosphodiesterase--in the colonic mucosa of the rat. Chronic ethanol consumption by feeding a nutritionally adequate liquid diet enhanced basal colonic adenylate cyclase activity significantly by 168% (p less than 0.01), but had no effect on colonic low Km cyclic AMP phosphodiesterase activity. In addition, various hormonal secretagogues were used to stimulate colonic adenylate cyclase. Colonic adenylate cyclase exhibited a significantly greater sensitivity and efficacy to prostaglandins and vasoactive intestinal peptide after chronic ethanol ingestion. Since increased intestinal cyclic AMP production due to an increased activity of intestinal adenylate cyclase is known to promote intestinal secretion of water and electrolytes, the frequently observed diarrhea in alcoholics may be explained at least in part by an enhanced production of colonic cyclic AMP.