[Anti-inflammatory effects of tea-flavonoids]. / Anti-inflammatorische Wirkungen der Tee-Flavonoide.

Tea flavonoids belong to the large group of polyphenols and display antioxidative, anti-inflammatory and anti-neoplastic activities. These phytochemicals are xenobiotics and are synthesized by tea plants such as Camellia sinensis and Camomilla recucita. These botanicals exhibit in vivo activities similar to that of biologicals which are widely used for chronic inflammatory diseases (rheumatoid arthritis, chronic inflammatory bowel disease). Epigallocathechin gallate and apigenin from these plants inhibit cytokines, chemokines and activated immune cells in vivo and in vitro. Clinical disorders with induced inflammatory pathways could benefit from flavonoid treatment. Dietary supplementation with specific tea-flavonoids could be used for Crohn's disease, ulcerative colitis and irritable bowel syndrome. Suppression of cytokine production could ultimately lead to inhibition of carcinogenesis. This mechanism could explain why flavonoids are effective in the prevention of intestinal neoplasia. This innovative new form of therapy should be tested in controlled, randomized clinical studies.

Expression of the glutathione enzyme system of human colon mucosa by localisation, gender and age.

BACKGROUND: The glutathione S-transferases (GST) can metabolise endogenous and exogenous toxins and carcinogens by catalysing the conjugation of diverse electrophiles with reduced glutathione (GSH). Variations of GST enzyme activity could influence the susceptibility of developing cancers in certain areas of the gastrointestinal tract. AIMS: The expression of the components of the glutathione system in the colon was investigated with respect to age, gender and localisation. METHODS: Biopsies of macroscopically normal mucosa from both proximal and distal colon were collected from 208 patients (106 females, 102 males; mean age 61 years), who underwent colonoscopy for various clinical reasons. GSH content, total GST enzyme activity and the levels of the GST isoenzymes glutathione S-transferase P1 (GSTP1) and glutathione S-transferase M1 (GSTM1) were determined. RESULTS: GST enzyme activity, GSH and GSTP1 levels decreased significantly from proximal to distal colon (GST activity: 264 vs. 244 nmol/min/mg protein, p < 0.001, GSH content: 32 vs. 30 nmol/mg protein, p = 0.022 and GSTP1 levels: 2.25 vs. 2.10 mug/mg protein, p < 0.001). In female patients there was a significant stepwise increase of GST-activities and GSTP1 levels from the age of under 50 years to over 70 years. Oral sex hormone substitution among female patients between 50 and 70 years suppressed GST-activities and GSTP1 content. CONCLUSIONS: The GSH-system in the colonic mucosa is expressed at a lower level in the distal colon (sigma) than in the colon transversum; whether this small difference translates into variations of incidence of colorectal cancer remains to be seen. Females express higher enzyme levels as they grow older, while in males no significant age effects were found. Elderly females might be better equipped with protective GSH-enzymes in the colon than males and this could contribute to the lower incidence of colorectal carcinomas in females.

Homocysteine, cysteine, and glutathione in human colonic mucosa: elevated levels of homocysteine in patients with inflammatory bowel disease.

The present study was performed to evaluate the levels of the amino thiols cysteine, homocysteine, and glutathione in the colonic mucosa of patients with various intestinal diseases, especially chronic inflammatory bowel disease. Colonic biopsies of macroscopically normal mucosa out of a proximal and distal segment were collected from 187 patients with various intestinal diseases. Protein was assayed in duplicate by the method of Lowry et al (1951), using bovine serum albumin as standard. Total glutathione, cysteine, and homocysteine were quantified by high performance liquid chromatography (HPLC) with fluorescent detection. Only in patients with inflammatory bowel disease were the homocysteine levels in the large bowel mucosa significantly elevated compared with the concentrations in patients with normal mucosa. No significant differences were seen for glutathione and cysteine concentrations in colonic mucosa among the different groups of diseases. No correlation was found between the age of the patients and levels of the amino thiols investigated. GSH content and concentrations of cysteine and homocysteine were similar in male and female subjects. In our study markedly elevated concentrations of homocysteine in the colonic mucosa were observed in patients suffering from ulcerative colitis and Crohn's disease. This finding has been reported already in the literature for plasma homocysteine levels. Increased homocysteine levels in the colonic mucosa and plasma of patients with inflammatory bowel disease may play a role in the pathogenesis of Crohn's disease and ulcerative colitis.

Influence of clinical factors, diet, and drugs on the human upper gastrointestinal glutathione system.

BACKGROUND: Glutathione (GSH) and the cytosolic glutathione S-transferases (GSTs) protect the gastrointestinal mucosa against the toxic effects of a wide variety of compounds, such as reactive oxygen species and electrophiles. AIMS: We wished to investigate the distribution along the upper gastrointestinal mucosa and the influence of clinical variables on components of the GSH system to learn more about factors which control its cytoprotective properties. METHODS: Antral and duodenal biopsies of normal appearing mucosa were collected from 202 patients (104 males, 98 females; mean age 62 years) undergoing upper gastrointestinal endoscopy. GSH content was examined by high pressure liquid chromatography, GST enzyme activity by 1-chloro-, 2, 4-dinitrobenzene conjugation, and levels of the GST classes alpha, pi, and theta by western blot. RESULTS: GSH, GST enzyme activity, and GST alpha levels were significantly lower (p<0.001) in the antrum than in the duodenum (antrum v duodenum: GSH 23.0 (0.7) v 35.0 (1.0) nmol/mg protein; GST activity 626 (19) v 832 (22) nmol/mg protein/min; GST alpha 4.5 (0.5) v 20.0 (0.7) microg/mg protein) while GST pi content was significantly higher (p<0.001) in antral than in duodenal biopsies (16.5 (0.7) v 11.2 (0.5) microg/mg protein). Antral GSH and GST activities were markedly lower in males compared with females (p<0.01). Some drugs (cisapride, diuretics, cortisol, analgesics) increased GST pi and GST alpha content but cytostatic drugs suppressed duodenal GST activity. High intake (>3 days a week) of vegetables enhanced duodenal GST alpha and GST pi and high intake of fruits the antral content of GST theta 1. CONCLUSIONS: The gastrointestinal GSH system represents the antitoxic barrier of the mucosa; its activity is influenced by localisation, sex, and drugs, and its enzymes are stimulated by a high intake of vegetables and fruits.

Pharmacokinetics of encainide in patients with cirrhosis.

The pharmacokinetics of encainide were investigated in 10 patients with cirrhosis and 10 matched controls following single intravenous (IV, 25 mg), single oral (so, 25 mg), and multiple oral (mo, 25 mg thrice daily over 5 days) dosing. The hepatic oxidative drug-metabolizing enzyme capacity and its inducibility were assessed by antipyrine elimination and 6-beta-hydroxycortisol excretion. Eight controls and nine patients were of the extensive metabolizer phenotype (EM), as assessed by the sparteine metabolic ratio. Statistics was performed in EM only. The antipyrine half-life was significantly longer and clearance was significantly lower in patients with cirrhosis. Following IV administration, no significant differences in encainide half-life clearance, volume of distribution, or the area under the plasma concentration time curve (AUC) were observed between patients and controls. Following so and mo, there was a fourfold reduction in the oral clearance in cirrhotics. Thus, encainide bioavailability was increased in cirrhosis. Whereas the AUC of encainide was significantly higher in patients, no differences were observed in its active metabolites, O-desmethyl-encainide (ODE) and 3-methoxy-O-desmethylencainide (MODE). Plasma concentrations of encainide and its metabolites after 3 and 5 days of mo suggested steady-state conditions after 3 days of oral dosing. No change in antipyrine elimination and 6-beta-hydroxycortisol excretion following mo occurred. There was no relationship between parameters of encainide and antipyrine elimination. In conclusion, even though the elimination of encainide was reduced in patients with cirrhosis, plasma levels of the pharmacologically active metabolites, ODE and MODE, were comparable.(ABSTRACT TRUNCATED AT 250 WORDS)

Antipyrine elimination and hepatic microsomal enzyme activity in patients with liver disease.

Induction of hepatic monooxygenases reflected by 7-ethoxycoumarin O-deethylase has been proposed to be associated with the initiation of liver damage. This study investigated a possible correlation between 7-ethoxycoumarin O-deethylase, reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase and benzypyrene hydroxylase activity in liver biopsy specimens of 31 patients with liver disease and antipyrine elimination, an in vivo parameter of hepatic monooxygenase activity. No correlation was found between the enzyme activities and antipyrine clearance or half-life. When microsomal enzyme activities were compared with the formation rate of 4-hydroxyantipyrine, 3-methylhydroxyantipyrine, and norantipyrine, a correlation was found only between benzo[alpha]pyrene hydroxylase and 3-methylhydroxyantipyrine (r = 0.89; p less than 0.0005). There was also a correlation between 7-ethoxycoumarin O-deethylase and reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase (0.56; p less than 0.05). Our data suggest that antipyrine elimination is not related to 7-ethoxycoumarin O-deethylase activity in liver disease. However, the formation rate of antipyrine metabolites, rather than antipyrine half-life and clearance, may correlate with the activity of certain microsomal enzymes.

Glutathione and its related enzymes in the small intestinal mucosa of rats: effects of starvation and diet.

Starvation for 24 h causes a striking fall in glutathione content from 3.19 +/- 0.27 to 1.88 +/- 0.14 (X +/- SEM) mumol/g tissue and of GGT activity from 31.75 +/- 4.17 to 19.49 +/- 3.13 (X +/- SEM) nmol/min/mg protein in the homogenate from whole mucosa of the upper small intestinal segments. This was associated with a significant increase in GSH-Px activity and the content of lipid peroxides (measured by the thiobarbituric assay). On semi-synthetic iron-supplemented diet the activities of GSH-T and GGT were significantly decreased as compared with crude diet. On semisynthetic iron-depleted diet GSH-T and GGT activities were further depressed, but this was accompanied with an additional depression of GSH, glutathione reductase (GSSG-R), and glutathione peroxidase (GSH-Px) activities and lipid peroxide concentrations. Food deprivation significantly lowers the mucosal GSH-content and could lead to a destabilization of this system presumably by increased oxidative stress. As compared to normal "crude" diet, semisynthetic diets and oral iron depletion have been shown to cause a depression of the intestinal GSH system. As a consequence of these effects, the resistance of the small intestinal mucosa toward exogeneous dietary toxins might be reduced.

[Benign symmetrical lipomatosis with polyneuropathy and mental performance deficits]. / Lipomatosis symmetrica benigna mit Polyneuropathie und Hirnleistungsdefiziten.

Lipomatosis symmetrica benigna is a rare condition, usually found in association with the complications of chronic alcoholism. A case is reported which showed the typical clinical picture, and diagnosis and therapy will are discussed.

Positive correlation between decreased cellular uptake, NADPH-glutathione reductase activity and adriamycin resistance in Ehrlich ascites tumor lines.

From a wild type strain of Ehrlich ascites tumor (EATWT) sublines resistant to daunorubicin (EATDNM), etoposide (EATETO), and cisplatinum (EATCIS) have been developed in vivo. Increase in survival and cure rate caused by adriamycin (doxorubicin) have been determined in female NMRI mice which were inoculated i.p. with EAT cells. Adriamycin concentrations causing 50% inhibition of 3H-thymidine (ICT) and 3H-uridine incorporation (ICU) and intracellular adriamycin steady-state concentrations (SSC) were measured in vitro. Adriamycin resistance increased and SSC decreased in the following sequence: EATWT - EATCIS - EATDNM - EATETO. When ICT and ICU were corrected for intracellular adriamycin concentrations in consideration of the different SSC (ICTc, ICUc), ICTc and ICUc still varied up to the 3.2 fold in EATCIS, EATDNM and EATETO in comparison to EATWT. Thus, in addition to different SSC other factors must be responsible for adriamycin resistance. Therefore, enzymes which may play a role in the cytotoxicity related to adriamycin metabolism (NADPH-cytochrome P-450 reductase, NADPH-glutathione reductase, NADP-glucose-6-phosphate dehydrogenase, NADP-isocitrate dehydrogenase) were measured. In contrast to the other parameters determined, NADPH-glutathione reductase was significantly (p less than 0.01) increased up to the 3.2 fold parallel to adriamycin resistance as determined by increase in life span, cure rate, ICTc, and ICUc, respectively. It is concluded that high activities of NADPH-glutathione reductase may contribute to an increase in adriamycin resistance of malignant tumors.

Inducing efficacy of ethanol on hepatic drug metabolizing enzymes in patients.

In liver biopsy material of eighty-nine patients with suspected liver disease the drug-metabolizing function was investigated. The capacity of the liver to oxidatively metabolize drugs was assessed by determination of cytochrome P-450 dependent monooxygenase activity in vitro. The biotransformational function of these microsomal enzymes was tested with compounds representing the activity of oxidative drug metabolism (7-ethoxycoumarin, p-nitroanisol and cytochrome c). From the eight-nine patients sixty-one had various liver diseases not related to ethanol and twenty-eight abused ethanol. When both groups were matched for age, sex, smoking, treatment with sedatives, drugs and degree of liver damage the alcoholic group had significantly higher activities of 7-ethoxycoumarin O-deethylase (EOD: 76.9 +/- 31.1 pmol min-1 mg-1 protein, mean +/- SD) than the non-alcoholic liver disease group (42.7 +/- 14.1). The inducing effect of ethanol was most striking on the EOD activity, less for the O-demethylation of p-nitroanisol (PNA) and not present for the NADPH-cytochrome c reductase. The induced patients were analysed in detail to find out which factors were responsible for the observed scatter of enzyme activities within the alcoholic group. Alcoholics with fatty liver (n = 7) had the highest EOD activities (108.9 +/- 25.0), patients with alcoholic hepatitis (n = 10) had significantly less activity (66.0 +/- 1.9) than the former group. However, alcoholics without liver damage (n = 6) had activities not significantly different (46.0 +/- 15.8) from controls (39.4 +/- 9.1). These subgroups among the alcoholics were comparable in terms of sex, age, smoking and drinking habits.(ABSTRACT TRUNCATED AT 250 WORDS)

[Differential diagnosis in fever of unknown origin: significance of concomitant clinical symptoms]. / Differentialdiagnose bei bisher ungeklärtem Fieber: Bedeutung klinischer Begleitsymptome.

Between 1978 and 1984, 169 patients were admitted to the hospital for fever of unknown origin which was repeatedly above 38.3 degrees C. After a retrospective analysis of their records the patients were divided into two groups on the basis of the following new criteria. The first group (74 patients) was described as having "monosymptomatic fever", i.e. fever without any other physical signs, whereas the second group (95 patients) had "polysymptomatic fever", i.e. fever with additional physical signs. In 56 patients (76%) of the monosymptomatic group fever had lasted longer than 3 weeks prior to admission. In 86% of these patients case history, physical examination, microbiological tests, serological tests for microorganisms and outoimune antibodies, and microscopic inspections of tissue and/or bone marrow led to a diagnosis. Malignancies, factitious fever and fever of unknown origin were found only in this group. The patients with malignancies were generally older than the rest of the patients (p less than 0.05), and eight of ten patients suffering from connective tissue diseases also had monosymptomatic fever. The incidence of infections in this group was 42% (31 cases), in contrast to 88% (84 cases) in the polysymptomatic group (p less than 0.05). Whereas the latter had significantly more bacterial infections (p less than 0.05), viral infections prevailed in the monosymptomatic group (p less than 0.05). Thus, the etiology of polysymptomatic fever distinctly differed from that of monosymptomatic fever. Since the frequency distribution of etiologies in the monosymptomatic group corresponded to that of the cases of fever of unknown origin in the literature, differentiation into monosymptomatic and polysymptomatic fever might be helpful in determining further diagnostic workup of patients with fever of unknown origin.

Effect of chlormethiazole on the hepatic monooxygenase enzyme system.

Ethanol abuse has been shown to induce hepatic monooxygenase activity. In order to study the effect of chlormethiazole on the hepatic monooxygenase enzyme system, the O-deethylation of 7-ethoxycoumarin was studied. Chlormethiazole was found to inhibit ethanol-induced monooxygenase activity.

Isolation of human hepatic microsomes and their inhibition by cimetidine and ranitidine.

Human hepatic microsomes were isolated from wedge biopsies of the liver from 13 patients undergoing abdominal surgery. Ultrasonic homogenisation was used to increase the yield of microsomal monooxygenase activity (7-ethoxycoumarin O-deethylase, NADPH-cytochrome c reductase), resulting in a 30% higher total enzyme activity per g liver than preparation by other techniques. In 4 individual microsomal preparations the influence of cimetidine and ranitidine on Michaelis-Menten kinetics of O-deethylation and of reductase activity were studied. Without the H2-receptor blocking drugs, enzyme kinetics of O-deethylation with a Km of 51.0 +/- 16.4 microM (n = 3) were obtained using Lineweaver-Burke plots. Both, cimetidine and ranitidine inhibited the O-deethylation; cimetidine had a five-fold higher inhibitory affinity (Ki 1.01 and 3.94 mM) to the monooxygenase than ranitidine (Ki 4.96 and 17.70 mM) in the uninduced liver. However, in liver from a patient with induced enzyme activity (Km = 478.0 microM), the Ki of ranitidine was similar to that of cimetidine (Ki ran 3.57 versus Ki cim 2.49 mM). The reductase activity was not inhibited by ranitidine and only marginally so by cimetidine. The results suggest that in human hepatic microsomes oxidative drug metabolism is inhibited by both H2-receptor antagonists. However, the inhibitory potency of the compounds seems to depend on the individual isozyme pattern of the hepatic microsomes. Thus, while cimetidine is an relatively nonspecific enzyme inhibitor, ranitidine might more selectively inhibit induced drug metabolizing enzymes.

Effect of rifampicin treatment on hepatic drug metabolism and serum bile acids in patients with primary biliary cirrhosis.

Six patients with primary biliary cirrhosis (PBC) were treated with a daily oral dose of 600 mg rifampicin for 2 weeks to induce the hepatic metabolism of drugs and bile acids. On rifampicin 5 of 6 patients experienced a pronounced decrease of their pruritus. In all patients the oxidative cytochrome P-450 dependent drug metabolism was induced as shown by an increase of antipyrine-clearance from 36.3 +/- 8.8 to 80.6 +/- 20.1 ml/min and an enhanced urinary excretion of 6-beta-hydroxycortisol from 454 +/- 1.99 to 1607 +/- 362 micrograms/24 h. Furthermore, in all 6 patients the serum alkaline phosphatase declined. In the 3 cholestatic patients (bilirubin greater than 1.0 mg/dl) the serum concentration of total and conjugated bile acids was strikingly reduced. Thus, rifampicin is an inducer of hepatic metabolism in PBC-patients, ameliorates the pruritus and can lower serum concentrations of alkaline phosphatase and bile acids.

Cyclophosphamide-induced remission in Weber-Christian panniculitis.

A patient with Weber-Christian panniculitis is described in this report in which treatment with prednisone and hydroxychloroquine caused no improvement of the disease, and even led to a worsening of the symptoms. In contrast, administration of oral cyclophosphamide led to a rapid remission of the disease. As Weber-Christian disease has no known aetiology and no specific treatment has been established, the successful therapy with the cytostatic drug cyclophosphamide may shed light on the pathogenesis of Weber-Christian panniculitis.