Comparative effects of indomethacin on hepatic enzymes and histology and on serum indices of liver and kidney function in the rat. (33/55)

The effects of high-dose indomethacin (three daily dose, 8.5 mg/kg ip) on pathology and histology, on serum and urine biochemistry, and on various hepatic enzyme activities were studied in rats. Hepatic cytochrome P-450 and aminopyrine N-demethylase were decreased by 52-62%, but glucuronyl transferase fell by only 22%. Hepatic glucose-6-phosphatase, aryl esterase, 6-phosphogluconate dehydrogenase and sulphotransferase remained unchanged, while glucose-6-phosphate dehydrogenase increased by 29%. There were no widespread changes in hepatic and renal pathology or histology, but noteworthy was a mild, focal, centrilobular hepatic response. By contrast, there were severe intestinal lesions: the effects on hepatic enzymes might have been partly a consequence of the intestinal damage. There was a reversible uraemia and significant decreases (20-40% below normal) in both serum albumin and protein, while serum levels of creatinine and aspartate-amino-transferase activity remained constant. A reversible N-acetyl-beta-D-glucoseaminidase (NAG) enzymuria occurred (300% above normal), but no significant proteinuria (less than 300 mg/l). Administration of 16, 16-dimethylprostaglandin F2 alpha(0.5 mg/kg iv) concomitantly with the indomethacin greatly ameliorated the intestinal lesions and prevented the decreases in hepatic drug-metabolizing enzymes. Concomitant 16,16-dimethylprostaglandin F2 alpha did not, however, influence the indomethacin-induced decreases in serum protein, albumin or NAG-enzymuria. It was concluded that indomethacin had a highly selective effect causing a decrease in hepatic cytochrome P-450, which was not accompanied by severe damage to hepatocyte structure.  (+info)

Depression of hepatic microsomal enzyme systems by lentinan in mice. (34/55)

Studies were performed to determine the effects of an immunopotentiating agent, lentinan, on the hepatic drug-metabolizing enzymes in mice. Lentinan was injected twice a day for two days, and the enzyme activities were determined 12 hr after the last injection of lentinan. A lentinan dose of over 0.25 mg/kg was required to cause a significant decrease (20-40%) in the hepatic microsomal aminopyrine N-demethylase and aniline hydroxylase activities. The loss of drug-metabolizing activity by the treatment with lentinan agreed with the loss of cytochrome P-450 content in many cases. Strain and substrate differences concerning the effect of lentinan on the metabolism of drug were also observed. That is to say, the loss of cytochrome P-450 content by the treatment with lentinan was observed in the ddY, C57BL/6 and BDF1 strain mice, but was not observed in the DBA/2, C3H/He and C57BL/10 strain mice. The decrease in the activities of 7-ethoxycoumarin O-deethylase and biphenyl 2-hydroxylase by the treatment with lentinan was considerably less than that of aminopyrine N-demethylase and aniline hydroxylase in ddY mice.  (+info)

Analytical study of microsomes and isolated subcellular membranes from rat liver. 3. Subfractionation of the microsomal fraction by isopycnic and differential centrifugation in density gradients. (35/55)

Rat liver microsomal fractions have been equilibrated in various types of linear density gradients. 15 fractions were collected and assayed for 27 constituents. As a result of this analysis microsomal constituents have been classified, in the order of increasing median density, into four groups labeled a, b, c, and d. Group a includes: monoamine oxidase, galactosyltransferase, 5'-nucleotidase, alkaline phosphodiesterase I, alkaline phosphatase, and cholesterol; group b: NADH cytochrome c reductase, NADPH cytochrome c reductase, aminopyrine demethylase, cytochrome b(5), and cytochrome P 450; group c: glucose 6-phosphatase, nucleoside diphosphatase, esterase, beta-glucuronidase, and glucuronyltransferase; group d: RNA, membrane-bound ribosomes, and some enzymes probably adsorbed on ribosomes: fumarase, aldolase, and glutamine synthetase. Analysis of the microsomal fraction by differential centrifugation in density gradient has further dissociated group a into constituents which sediment more slowly (monoamine oxidase and galactosyltransferase) than those of groups b and c, and 5'-nucleotidase, alkaline phosphodiesterase I, alkaline phosphatase, and the bulk of cholesterol which sediment more rapidly (group a2). The microsomal monoamine oxidase is attributed, at least partially, to detached fragments of external mitochondrial membrane. Galactosyltransferase belongs to the Golgi complex. Group a2 constituents are related to plasma membranes. Constituents of groups b and c and RNA belong to microsomal vesicles derived from the endoplasmic reticulum. These latter exhibit a noticeable biochemical heterogeneity and represent at the most 80% of microsomal protein, the rest being accounted for by particles bearing the constituents of groups a and some contaminating mitochondria, lysosomes, and peroxisomes. Attention is called to the operational meaning of microsomal subfractions and to their cytological complexity.  (+info)

Glucose dehydrogenase (hexose 6-phosphate dehydrogenase) and the microsomal electron transport system. Evidence supporting their possible functional relationship. (36/55)

The ability of a microsomal enzyme, glucose dehydrogenase (hexose 6-phosphate dehydrogenease) to supply NADPH to the microsomal electron transport system, was investigated. Microsomes could perform oxidative demethylation of aminopyrine using microsomal glucose dehydrogenase in situ as an NADPH generator. This demethylation reaction had apparent Km values of 2.61 X 10(-5) M for NADP+, 4.93 X 10(-5) m for glucose 6-phosphate, and 2.14 X 10(-4) m for 2-deoxyglucose 6-phosphate, a synthetic substrate for glucose dehydrogenase. Phenobarbital treatment enhanced this demethylation activity more markedly than glucose dehydrogenase activity itself. Latent activity of glucose dehydrogenase in intact microsomes could be detected by using inhibitors of microsomal electron transport, i.e. carbon monoxide and p-chloromercuribenzoate (PCMB), and under anaerobic conditions. These observations indicate that in microsomes the NADPH generated by glucose dehydrogenase is immediately oxidized by NADPH-cytochrome c reductase, and that glucose dehydrogenase may be functioning to supply NADPH.  (+info)

Studies of metabolic fate of a new antiallergic agent, azelastine (4-(p-chlorobenzyl)-2-[N-methylperhydroazepinyl-(4)]-1-(2H)-phthalazinone hydrochloride). (37/55)

The metabolic fate of a new antiallergic agent, azelastine (4-(p-chlorobenzyl)-2-[N-methylperhydroazepinyl-(4)]-1-(2H)-phthalazinone hydrochloride) in rats and guinea pigs was investigated using its 14C-labelled compound. The blood level of radioactivity reached the maximum at 1-1.5 hr after oral administration, indicating the rapid absorption of the drug from gastrointestinal tract. A high concentration of radioactivity was detected in the lung of both species following either oral or intravenous administration. The major pathway of excretion of radioactivity was by way into feces, in both species. The radioactivity excreted in feces was attributable to that which was excreted in bile and exsorbed into gastrointegtinal tract. When the drug was given to pregnant rats, the concentration of radioactivity in the fetus was significantly lower than those in placenta and uterus, indicating the limited placental transfer of the drug. The successive oral administration of the drug in lower doses exerted no effect on the activity of microsomal drug-metabolizing enzymes of rat liver, while in higher doses, had a slight effect.  (+info)

Effect of lipopolysaccharide (from Escherichia coli) on the hepatic drug-metabolizing activities in successively LPS-treated mice. (38/55)

The effect of an acute or a successive administration of endotoxin (lipopolysaccharide obtained from Escherichia coli, LPS) on the hepatic drug-metabolizing system in vivo and in vitro was examined in mice. An acute LPS (5 mg/kg, i.v.) administration or a successive LPS (5-20 mg/kg, i.p., a day for 6 days) administration prolonged the duration of pentobarbital sleeping time and reduced the rate of hepatic microsomal metabolism of pentobarbital, aminopyrine, aniline and cyclophosphamide and reduced cytochrome P-450 content as compared with those in the control mice. No change of these parameters, however, was observed by an acute treatment with LPS to the successively LPS-treated mice. In addition, the LD50's of aminopyrine and pentobarbital and the ED50 of aminopyrine were reduced by an acute administration of LPS in control mice. No change of both parameters, however, was observed in the successively LPS-treated mice with or without an acute administration of LPS.  (+info)

Studies on certain drug-metabolizing enzymes in deoxypyridoxine-treated rats. (39/55)

The effect of deoxypyridoxine on the activities of drug-metabolizing enzymes was investigated in male rats. Phenylbutazone oxidase and aminopyrine N-demethylase decreased in both liver and kidney of deoxypyridoxine-treated rats that received either an 18% or 8% casein diet. However, the magnitude of decrease in activities was more when the rats received an 8% casein diet. The NADPH oxidase activity remained unchanged following deoxypyridoxine treatment. The diminished activities of phenylbutazone oxidase and aminopyrine N-demethylase noted after deoxypyridoxine treatment were restored by pyridoxine supplementation. The decreased activities of drug-metabolizing enzymes in deoxypyridoxine treated rats were not reversed by thyroxine supplementation. It is suggested that pyridoxine in the form of pyridoxal phosphate might be involved in the regulation of drug-metabolizing activities.  (+info)

Metabolism of aflatoxin B1 in the isolated nuclei of rat liver. (40/55)

The nuclear biotransformation of aflatoxin B1 in vitro was observed with regard to inducer specificity, pH dependency, time course, kinetics, inhibitor sensitivity, and nuclear localization, and these data were compared with those from the microsomal transformation of aflatoxin B1. The nuclei and microsomes are capable of metabolizing aflatoxin B1 into aflatoxin M1, aflatoxin Q1, and two unidentified fluorescent compounds in the presence of fortified NADPH generating system. Pretreatments of rats by 3-methylcholanthrene or polychlorinated biphenyl enhanced both the nuclear and microsomal C-9 alpha-hydroxylation of aflatoxin B1 into aflatoxin M1 and phenobarbital or polychlorinated biphenyl induced aflatoxin Q1 production. The optimal pHs for aflatoxin M1 and Q1 were 8.3 and 7.4, respectively, both in the nuclei and microsomes. Kinetic analysis revealed the Km of aflatoxin M1 formation in methylcholanthrene-induced nuclei was 9.4 x 10(-5) M, and this value was very close to that obtained with the microsomes. Inhibitor experiments revealed a high sensitivity of aflatoxin M1 formation to 7,8-benzoflavone and a low sensitivity of aflatoxin Q1 to SKF 525A. These findings and data on the detergent treatment of nuclei suggest that the nuclear cytochrome P-448 system, induced by 3-methylcholanthrene and localized in the outer membrane, catalyzes the aflatoxin M1 formation, and the cytochrome P-450 system induced by phenobarbital biotransforms aflatoxin B1 into aflatoxin Q1. Pretreatment of rats by phenobarbital was found to induce microsomal degradation or detoxication of aflatoxin B1 into water-soluble metabolites, and no such an induction was observed in the nuclei.  (+info)