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Biomedical subjects

M Ahotupa

Publications and source records attributed to M Ahotupa.

At least 73 records · Page 4Linked to original sources
PubMed1990

Quantity and saturation degree of dietary fats as modulators of oxidative stress and chemically-induced liver tumours in rats.

Male rats were fed, from weaning onwards, either 2, 12.5 or 25% sunflower seed oil (polyunsaturated fatty acids, PSA) or lard (saturated fatty acids, SFA) and from the age of 15 weeks subgroups were given N-nitrosodimethylamine (NDMA) for 30 weeks. Blood levels of lipids were assayed and during the study exhaled ethane was measured as an index of in vivo lipid peroxidation (LPO). At the age of 50 weeks, rats were killed and livers were analysed for tumours. PSA diets decreased plasma cholesterol and triglyceride concentrations vs. respective SFA diet; NDMA administration did not affect plasma cholesterol but enhanced triglyceride concentration. NDMA markedly enhanced LPO. An increase in dietary fat content from 2 to 25% enhanced ethane exhalation, more in rats fed PSA than the SFA diet. In the 25% PSA group, indomethacin in the diet strongly inhibited LPO. Prevalence of liver haemangiosarcomas increased from 42% to 80% (p less than 0.05) in NDMA-treated animals when PSA increased from 2 to 25%; in the group having a 25% PSA diet containing indomethacin, the NDMA-induced tumour incidence was reduced to 64%. In NDMA-treated rats fed SFA diets the prevalence of haemangiosarcoma increased from 43% (2% fat) to 67% (25% fat). The data show that NDMA modifies plasma lipids and increases LPO. The quantity and saturation degree of fats altered the frequency of chemically-induced tumours and modified LPO. As an index of free radical reactions, LPO may have an important role in carcinogenesis. Dietary fat thus appears to promote carcinogenesis through mechanisms that involve LPO.

Animals↗
PubMed1988

Long-lasting effects of tobacco smoking on pulmonary drug-metabolizing enzymes: a case-control study on lung cancer patients.

Lung tissue specimens were taken during surgery from middle-aged men with either lung cancer (LC, n = 54) or a nonneoplastic lung disease (n = 20). Aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin O-deethylase (ECDE), epoxide hydrolase (EH), glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UDPGT) activities and glutathione and malondialdehyde contents were determined in 12,000 X g supernatant fractions from nontumorous parenchymal tissues. Interindividual differences in enzyme activities ranged from 11- to 440-fold, and glutathione content varied by 17-fold; the values showed unimodal distributions. AHH, ECDE, EH, and UDPGT activities were significantly and positively correlated to each other; a significant negative correlation was found between GST and the other enzymes. A relationship between enzyme activity and number of cigarettes smoked (pack-years) was found only for GST. Ignoring detailed smoking histories in the 6-month period preceding surgery, no difference was found in enzyme activities or glutathione content between LC and nonneoplastic lung disease patients or between smokers and nonsmokers. However, when the number of days since stopping smoking was considered, in smokers a significant increase was found for AHH, EH, and UDPGT activities and a significant decrease was found for GST activity, as compared to nonsmokers. LC patients who had smoked until the day before surgery had higher activities of AHH, ECDE, EH, and UDPGT than nonsmokers, while GST activity was reduced by one-third. The activities of these enzymes returned to the basal level found in nonsmokers within 59 (AHH), 108 (EH), 67 (UDPGT), and 40 (GST) days. LC patients who were recent smokers (within 30 days prior to surgery) had significantly induced AHH and ECDE activities when compared with smoking nonneoplastic lung disease patients. These results show that pulmonary drug metabolism can be altered by tobacco smoking and that these effects can last 40 to 108 days after cessation of smoking. These new findings should be considered in studies on the role of carcinogen-metabolizing enzymes in determining susceptibility to lung cancer.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1987

Monoclonal antibody characterization of hepatic and extrahepatic cytochrome P-450 activities in rats treated with phenobarbital or methylcholanthrene and fed various cholesterol diets.

Monoclonal antibodies (MAb) against 3-methylcholanthrene (MC)- and phenobarbital (PB)-inducible forms of cytochrome P-450 isozyme were used to characterize changes in aryl hydrocarbon hydroxylase (AHH) and ethoxycoumarin O-deethylase (ECDE) activities modulated by dietary cholesterol. Rats were induced by MC or PB, and immunochemical inhibition of AHH and ECDE activities was studied as an indication of changes in cytochrome P-450 isozyme patterns. Feeding of a cholesterol-free diet markedly decreased enzyme activities both in liver and in small intestinal mucosa, and the highest activities were observed after feeding rats a high (2%)-cholesterol diet for one month. As a control, a normal pelleted diet (0.1% cholesterol) was used; in rats fed this diet, intermediate levels of monooxygenase activities were present. Although no diet-dependent change in total AHH and ECDE activities was observed in kidneys and lungs, diet apparently modulated isozyme composition in the lungs, as indicated by a change in the immunochemical inhibition pattern with MAb; no such shift was observed in the kidneys. In liver and intestine, in addition to changes in total activity, isozyme composition was also altered, as indicated by inhibition of the catalytic activities of cytochrome P-450 by MAb. Our data infer that dietary cholesterol can: (i) modulate total monooxygenase activities, especially in the intestine; (ii) change the cytochrome P-450 isozyme composition in liver and intestine; (iii) change isozyme composition without changing overall enzyme activity, e.g. in lungs; and (iv) have no effect in a tissue (e.g. kidney) that lacks constitutionally the P-450 isozyme responsive to cholesterol.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1987

Rapid oxidative stress induced by N-nitrosamines.

We have investigated the generation of prooxidant state shortly after administration of N-nitrosamines (NA) to rats. N-Nitrosodimethylamine (NDMA) was found to increase ethane exhalation (EE) rapidly in a dose-related manner. EE remained elevated for several days after single doses of NDMA. Similarly, lipid peroxidation (LP) in the liver (measured by four methods) increased rapidly showing a peak 20 min after NDMA dose. The increase of LP was preceded by a decrease in retinol concentration in the liver. N-Nitrosodiethanolamine, too, increased EE and LP in the liver, whereas N-nitrosomethylbenzylamine had no effect. Thus, hepatocarcinogenic NA induced LP in their target tissue, and the LP enhancing effects of NA were not related to their acute toxic effects.

Animals↗
PubMed1987

Elevated lipid peroxidation in rats induced by dietary lipids and N-nitrosodimethylamine and its inhibition by indomethacin monitored via ethane exhalation.

The effect of dietary lipids alone or in combination with an administered carcinogen, N-nitrosodimethylamine (NDMA), on whole body lipid peroxidation was studied in rats in vivo. Groups of rats were fed diets containing 2%, 12.5%, or 25% of either saturated or polyunsaturated fat. Lipid peroxidation in individual animals was determined by measuring the concentration of ethane in exhaled air. Increased ethane exhalation was found in rats when the amount of dietary fat was increased from 2% to 12.5%, but animals receiving 12.5% or 25% fat in the diet exhaled ethane at similar rates. Rats consuming polyunsaturated fat exhaled more ethane than those eating saturated fat. In all groups, NDMA administration drastically increased ethane exhalation. Indomethacin completely blocked the increase in ethane exhalation caused by dietary lipids.

Animals↗
PubMed1987

Lipid peroxidation induced by N-nitrosodimethylamine (NDMA) in rats in vivo and in isolated hepatocytes.

To investigate the role of carcinogenic chemicals as a possible cause for oxidative damage, rats were treated with N-nitrosodimethylamine (NDMA) and various measures of lipid peroxidation were followed. As an indication of enhanced peroxidative processes in vivo, NMDA treatment produced rapidly an increase in the rate of ethane exhalation. A single i.p. or p.o. injection of 10 mg/kg b.w. elevated ethane exhalation by 13-14 fold; a single dose of 0.5 mg/kg of NDMA (the smallest dose tested) increased 5-fold the amount of ethane exhaled. Similarly, lipid peroxidation in the liver of NDMA-treated rats (measured by diene conjugation, chemiluminescence, the production of fluorescent and TBA-reactive material) was found to be increased rapidly showing a peak already 20 min after dosing. Simultaneously, NDMA-treatment slightly decreased antioxidant enzyme activities and GSH contents in the liver. In isolated rat hepatocytes the lucigenin-dependent chemiluminescence, as well as H2O2 release, were increased by micromolar concentrations of NDMA. Finally, it was shown that the rate of NADPH-stimulated ethane production by hepatic microsomes, prepared from untreated rats, was increased in the presence of NDMA. Thus, our results demonstrate that the alkylating NDMA can induce oxidative stress in rodents. Whether the same is true for other classes of carcinogens and processes known to affect tumor initiation/progression is presently under investigation.

Animals↗
PubMed1985

Enhanced peroxisomal beta-oxidation of fatty acids and glutathione metabolism in rats exposed to phenoxyacetic acids.

Peroxisomal beta-oxidation of fatty acids and the activities of glutathione-metabolizing enzymes in rat liver were measured after administration of 2,4-dichlorophenoxyacetic acid (2,4-D), 4-chloro-2-methylphenoxyacetic acid (MCPA), clofibrate [ethyl], 2-(p-chlorophenoxy)-2-methylpropionate], glyphosate (N-phosphonomethyl glycine, a herbicide not structurally related to phenoxy acids) or saline for 14 days. beta-Oxidation increased by 6-fold in the group given clofibrate, 3-fold in the 2,4-D-treated group, and 2-fold in the MCPA-treated group over the level in the controls (saline-treated). Glyphosate did not increase beta-oxidation. No significant change in reduced glutathione content from that in controls was found in any of the treated groups. Glutathione reductase activity increased by about 40% after administration of either 2,4-D or MCPA, and glutathione peroxidase activity increased by 30% in animals given MCPA. A slight decrease in glutathione S-transferase activity was found in the group treated with clofibrate. The marked increases in peroxisomal beta-oxidation of fatty acids were accompanied by only minor changes in the activities of enzymes involved in glutathione-dependent inactivation of organic hydroperoxides and other oxygen-centred reactive agents.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1983

Adipose tissue content as a modifier of the tissue distribution, biological effects, and excretion of a hexachlorobiphenyl in C57BL/6J and DBA/JBOMf mice.

C57BL/6J (C57) and DBA/JBOMf (DBA) mice were used to study the role of adipose tissue as a modifier of tissue distribution, biological effects, and elimination of a lipophilic foreign chemical, 2,4,5,2',4',5'-hexachlorobiphenyl (HCB). As an indication of biological potency of the model compound, the activities of hepatic drug-metabolizing enzymes were determined. DBA mice contained twice as much body fat as C57 mice. Since the highly lipophilic HCB was primarily sequestered by the adipose tissue, DBA mice required greater doses of HCB than did C57 mice to reach similar tissue levels of the chemical. Accordingly, greater HCB doses were required by DBA mice for elevation of drug-metabolizing enzyme activities. Phenobarbital elevated enzyme activities in a similar way in both mouse strains. When the dietary intake of DBA mice was restricted, the body fat content decreased from 15% to 5% of body weight during 1 week. In these animals the tissue accumulation of HCB and enzyme induction resembled the situation in C57 mice fed ad libitum. Highest elevations were seen in the activities of 7-ethoxycoumarin-O-deethylase and arylhydrocarbon hydroxylase (EC 1.14.14.2). In addition, the activity of epoxide hydrolase (EC 3.3.2.3) was increased, whereas glutathione S-transferase as well as UDP-glucuronosyltransferase (EC 2.4.1.17) activities remained unchanged. The abundant adipose tissue content played no role in the nonresponsiveness of DBA mice to 3-methylcholanthrene since, in contrast to C57 mice, no changes in enzyme activities were detected in DBA mice deprived of food, even after large doses of 3-methylcholanthrene. The adipose tissue content also affected the rate of elimination of HCB. DBA mice excreted smaller quantities of HCB than did C57 mice after equal doses. When, however, fasted DBA mice received HCB, they excreted it at rates similar to those of C57 mice fed ad libitum. In C57 mice, concomitant to the elevation of monooxygenase activities, there was an increase in the rate of excretion of HCB. No such elevation could be seen after a dose that was too small to elevate enzyme activities.

Adipose Tissue↗
PubMed1982

Dietary cholesterol-induced changes of xenobiotic metabolism in liver. II. Effects of phenobarbitone and carbon tetrachloride on activities of drug-metabolizing enzymes.

The influence of dietary cholesterol on drug metabolism was studied by feeding rats either a cholesterol-free or a high (2%) cholesterol diet for 4 weeks from weanling onward and giving phenobarbitone (Pb) and/or carbon tetrachloride (CCl4) thereafter. Pb was given in drinking water for 7 days at a dosage of 100 mg/kg and CCl4, at a dosage of 1.5 mg/kg SC 6 days before assays of drug-metabolizing enzymes. The cytochrome P-450 concentration was 2-fold in rats fed the 2% cholesterol diet in comparison with those fed the cholesterol-free diet. Only a weak induction by Pb was found in the cholesterol-free group. Only slight differences due to the cholesterol diets or due to the administration of xenobiotics were found in the NADPH cytochrome c reductase activity. The PPO hydroxylase activity was 2-fold in the livers of rats fed the 2% cholesterol diet in comparison with those fed the cholesterol-free diet. In the ethoxyresorufin deethylase activity, differences between diets were present first after the administration of xenobiotics. No change in the hepatic aryl hydrocarbon hydroxylase activity was found due to changes in the cholesterol content of the diets. The ethoxycoumarin O-deethylase activity was 2-fold in the livers of rats fed 2% cholesterol diet from those fed the cholesterol-free diet. The inducibility of ethoxycoumarin O-deethylase was equal, regardless of which diet was used. The hepatic epoxide hydrolase activity of rats fed 2% cholesterol was 3-fold in comparison with the cholesterol-free group. The inducibility by Pb was higher in the livers of the cholesterol-free (3.3-fold) than 2% cholesterol-fed rats (2.4-fold). The hepatic UDP-glucuronosyl-transferase activity was 1.5-fold in 2% cholesterol-fed rats in comparison with rats fed the cholesterol-free diet. The inducibility by CCL4 was found only in rats fed the cholesterol-free diet. The results suggest that dietary cholesterol modifies the enzyme activities in the liver and modifies their response to enzyme inducers.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1982

Dietary cholesterol-induced changes of xenobiotic metabolism in liver. I. Influence of xenobiotic administration on hepatic membrane structure.

We have studied the effects of dietary lipids on the structure and function of hepatic endoplasmic reticulum by feeding rats either with a 2% cholesterol or cholesterol-free diet. Rats were further administered either phenobarbitone, carbon tetrachloride, or both in combination to reveal possible differences in the response of the microsomal membranes to xenobiotics. Cholesterol feeding increased the membrane cholesterol contents and also carbon tetrachloride increased microsomal cholesterol contents in those rats fed a cholesterol-free diet. Also the microsomal phospholipid contents were higher in those rats fed 2% cholesterol diet than in those fed cholesterol-free diet and in the 2% cholesterol group also phenobarbitone increased the phospholipid contents. In addition, there were changes in the phospholipid-fatty acid proportions between rats fed 2% cholesterol and cholesterol-free diets. When 1,8-ANS was used as a fluorescence probe, phenobarbitone increased the fluorescence in both the dietary groups, while carbon tetrachloride decreased it; less change was present using PNA as a substrate. When Scatchard plots were constructed phenobarbitone changed the turning point more in the cholesterol-free group than in the 2% cholesterol group, while reversed orders of changes were found with carbon tetrachloride. The results demonstrated that dietary cholesterol has profound effects on the structure of microsomal membranes far beyond changes in their cholesterol content. The membrane fluidity also changes owing to alterations in the phospholipid contents and in their fatty acid composition.

1-Naphthylamine↗
PubMed1980

Effect of metal salts on UDPglucuronosyltransferase activity of various aglycones in rat liver microsomes in vitro.

The effects of aluminium, manganese, ferrous and ferric iron, cobalt, nickel, copper, zinc, cadmium, barium, mercury and lead ions on the rat hepatic UDPglucuronosyltransferase activity with regard to 4-methylumbelliferone, 4-nitrophenol, bilirubin, and 2-aminophenol were investigated in vitro. Conjugation of bilirubin was found to be activated by manganese, cobalt, nickel, cadmium, mercury and lead ions in native microsomes, but not in digitonin-treated microsomes. Aluminum, ferrous iron, cadmium, barium and lead increased the conjugation of 4-nitrophenol in native microsomes and aluminium in digitonin-treated microsomes as well. Lead slightly activated 4-methylumbelliferone conjugation, whereas none of the metal salts studied were found to activate the conjugation of 2-aminophenol. Copper and zinc salts inhibited all conjugations. In digitonin-treated microsomes, the conjugation of 4-nitrophenol was inhibited by cadmium and mercury, that of 4-methylumbelliferone by nickel and lead as well. The sensitivity of 4-methylumbelliferone conjugation to inhibition by mercury was most pronounced in microsomes prepared from rats pretreated with 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Aminophenols↗
PubMed1979

Effects of tetraethyl lead on the activities of drug metabolizing enzymes in different tissues of the rat.

The present study describes the effects of tetraethyl lead on various drug metabolizing enzymes in different tissues of the rat. Tetraethyl lead was administered intraperitoneally to rats (250 mumol/kg) on two consecutive days. The animals were killed on day 3. Tetraethyl lead-treatment decreased the concentration of hepatic cytochrome P-450 (to 45 per cent of the control), the hepatic activity of aryl hydrocarbon hydroxylase (to 41 per cent of the control) and ethoxycoumarin deethylase (to 45 per cent of the control). Epoxide hydratase activity was enhanced in the liver (1.3-fold), kidney (3.3-fold), and small intestinal mucosa (4.7-fold). The activity of glutathione S-transferase decreased in the liver (to 69 per cent of the control) but increased in the kidney (1.5-fold) and small intestinal mucosa (1.7-fold). The glucuronidation of o-aminophenol was enhanced (2.2-fold) in the kidney of tetraethyl lead treated rats. It is concluded that exposure to tetraethyl lead brings about widespread changes in the ability of mammals to detoxify foreign compounds.

Animals↗
PubMed1978

Induction of arylhydrocarbon hydroxylase and UDP glucuronosyl transferase by PCB in hepatic cell cultures.

The purpose of the investigation was to derive a hepatic cell line to be used in induction studies of drug metabolizing enzymes. Two pure cell lines were isolated from primary liver cell cultures, one with an epithelial-like appearance, the other with a fibroblast-like appearance. The specific activities of arylhydrocarbon hydroxylase (AHH) and UDP glucuronosyl transferase (UDPGT) were greater in hepatocyte cultures than in primary cultures or in fibroblast cultures. PCB enhanced the activity of AHH and UDPGT in hepatocyte cultures. These results indicate that cultured hepatocytes can be used to study the effect of PCB on drug metabolizing enzymes.

Animals↗