Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aryl hydrocarbon hydroxylase activity was detectable in cultured macrophage monolayers of peripheral blood monocyte origin. Peripheral blood monocytes were isolated from patients with biopsy-confirmed liver disease and healthy volunteers. Macrophage monolayers were prepared and incubated at 37 degrees C. After 24 hr, the aryl hydrocarbon hydroxylase activity and cellular protein concentration were assayed on cell homogenates. The monocyte aryl hydrocarbon hydroxylase activity in cultured macrophages from normal volunteers was 1.23 +/- 0.16 (n = 19). The aryl hydrocarbon hydroxylase activity in macrophage cultures from patients with biopsy-confirmed liver disease was 0.48 +/- 0.05 (n = 20). This represents a significant (61%) decrease in monocyte aryl hydrocarbon hydroxylase compared to controls. The 20 patients have established cirrhosis or early stage liver disease. The established cirrhosis group includes alpha 1-antitrypsin deficiency-associated cirrhosis; primary biliary cirrhosis; alcoholic (Laennec's) cirrhosis; cryptogenic cirrhosis, and hemochromatosis. Early stage liver disease is attributed to methotrexate (Stage III), early stage primary biliary cirrhosis and alpha 1-antitrypsin deficiency. Our results indicate that the depression in monocyte aryl hydrocarbon hydroxylase activity is greater in patients with established cirrhosis than early stage liver disease. Our results further suggest that cultured monocytes from patients with liver disease spontaneously release soluble factors into the culture medium. Incubation of this medium, containing macrophage factors, with isolated hepatocytes significantly depress hepatocyte aryl hydrocarbon hydroxylase activity compared to medium obtained from cultures of monocytes from normal volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Depression of peripheral blood monocyte aryl hydrocarbon hydroxylase activity in patients with liver disease: possible involvement of macrophage factors. 355 13

Administration of a single intraperitoneal dose of 1,1-dichloroethylene (125 mg/kg, 1,1-DCE) to mice resulted in bronchiolar injury with selective necrosis of Clara cells. Degenerative changes were manifest in Clara cells as early as 1 h following 1,1-DCE exposure, and were characterized by marked swelling of mitochondria and aggregation of chromatin against the nuclear membrane. Cell death was apparent at 2 h; by 8 h, areas of the bronchiolar epithelium were devoid of lining cells, and at 24 h, the majority of Clara cells were exfoliated. The residual epithelium consisted of flattened cells which formed a thin lining for the airway. Necrosis of Clara cells early in the course of 1,1-DCE exposure coincided with peak covalent binding of [14C]1,1-DCE and significant depression of components of the pulmonary mixed-function oxidase system; cytochrome P-450 and aryl hydrocarbon hydroxylase activity were markedly reduced but not depleted. Liver damage involving centrilobular hepatocytes was observed at 24 h in 30% of treated animals, and coincided with significant inhibition of aryl hydrocarbon hydroxylase activity; cytochrome P-450 content, however, remained unchanged. While changes in the liver evoked by 1,1-DCE were less striking, the results in lung demonstrate positive temporal correlations between structural damage, peak covalent binding and disturbances of monooxygenase enzymes.
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PMID:Pulmonary toxicity of 1,1-dichloroethylene: correlation of early changes with covalent binding. 369 28

A novel effect of metal ions in the brain is described. Mn was found to alter heme metabolism and the cytochrome P-450-dependent mixed-function oxidase activities in rat brain. A more than 2-fold increase in benzo(alpha)pyrene hydroxylase and 7-ethoxycoumarin deethylase activities were observed in the brain of rats treated for 7 days with Mn. The increases were regionally distributed; the highest elevations were observed in the hippocampus, pons and the caudate putamen. Moreover, in rats treated with Mn for 1 or 7 days a marked depression in the activity of the mitochondrial ALA synthetase was observed. The activity of the microsomal heme oxygenase was also inhibited at 7 days, but not 1 day, after Mn treatment. These inhibitions were reflected in an initial decrease, followed by a rebound return to normal, in the concentration of cytochrome P-450 in the brain. Mn was ineffective in vitro in altering heme and drug metabolism activities. It is suggested that Mn-mediated alterations in heme metabolic activities promote changes in the composition of cytochrome P-450 species in the brain microsomal fractions, such that the relative concentrations of the molecular species which catalyse aryl hydrocarbon hydroxylase activity become selectively increased.
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PMID:Regulation of heme and drug metabolism activities in the brain by manganese. 392 Oct 22

Chrysotile asbestos fibers impair the activities of rat liver microsomal aryl hydrocarbon hydroxylase (AHH), aminopyrine (AP) N-demethylase and dimethylnitrosamine (DMN) demethylase in vitro. This inhibition is concentration-dependent. Preincubation of 3-methylcholanthrene (3-MC)-pretreated rat liver microsomes with chrysotile depresses the overall metabolism of [G-3H]benzo[a]pyrene (BaP). Various forms of asbestos employed inhibit AHH activity to the same extent. However, other types of asbestos are not as effective as chrysotile in diminishing AP demethylase activity. Chrysotile and crocidolite fibers are not found to significantly change the apparent Km of AHH activity, from 3-MC-pretreated rat liver microsomes, for BaP. Increasing the microsomal protein concentration partially abolishes the inhibition of AHH activity caused by chrysotile fibers. Inhibition of AP demethylase and AHH activities is attenuated by bovine serum albumin (BSA) or ferritin. Depression of AHH activity by crocidolite is significantly reversed by ferritin. Since polymers such as ferritin override enzyme inhibition by chrysotile as well as crocidolite, surface chemical groups of the fibers may be involved in enzyme modification.
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PMID:Effect of asbestos fibers on aryl hydrocarbon hydroxylase and aminopyrine N-demethylase activities of rat liver microsomes. 394 7

At a high dose, cyclophosphamide (Cy, 200 mg/kg) causes depression of the enzyme activity of the hepatic mixed function oxygenase (MFO) system in Sprague-Dawley rats. The present report provides evidence for the early regeneration of the depleted enzyme activity in Cy-treated rats by purified protein A (P) of Staphylococcus aureus. Enzymes of the MFO system, such as aminopyrine demethylase and aryl hydrocarbon hydroxylase, were assayed and the content of cytochrome P-450 was determined. Inoculation of P (60 micrograms/kg) prior to Cy inoculation provides a better effect than P administration after Cy. The exact mechanism of P action is unknown. P-treated animals appear to have an ability to repair the damage caused by the toxic metabolites of Cy earlier than those in the Cy group. This property of protein A may become useful in accelerated regeneration of the enzyme activity in the hepatic MFO system following the toxic insult of Cy metabolites.
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PMID:In vivo protection by protein A of hepatic microsomal mixed function oxygenase system of cyclophosphamide-treated rats. 397 77

A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to further investigate the effects of traumatic injury on the hepatic cytochromes P-450. In vitro drug metabolism studies with hexobarbital and zoxazolamine as substrates confirmed the post-traumatic depression of the cytochrome P-450-catalyzed oxidation of these drugs which was suggested by previous in vivo pharmacokinetic studies. Enzyme kinetic studies revealed diminished Vmax values with no change in Km, a finding which would seem to concur with the previously demonstrated decrease in hepatic cytochrome P-450 content after model trauma. Moreover, a battery of in vitro microsomal monooxygenase assays demonstrated that model trauma exerted a differential effect on various hepatic cytochrome P-450 isoenzymes. This phenomenon was confirmed by anion-exchange HPLC of solubilized hepatic microsomal hemoproteins. One of the most interesting aspects of this selective effect on cytochrome P-450 subtypes was the relative induction of cytochrome P-448 content and activity, in contrast to the variable decrease seen with cytochrome P-450 activities. The potential in vivo sequelae of this differential influence were suggested by changes observed in the urinary metabolic profile of antipyrine after model trauma.
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PMID:Effects of model traumatic injury on hepatic drug metabolism in the rat. III. Differential responses of cytochrome P-450 subpopulations. 614 9

The effects of pretreatment with 3-methylcholanthrene (MC) and beta-naphthoflavone (beta NF) on the hepatic microsome-mediated mutagenesis of aflatoxin B1 (AFB1) and benzo[a]pyrene, and on the metabolism of aflatoxins B1 and B2, were investigated in inbred mouse strains. The inbred strains of mice studied included Ah nonresponsive strains (DBA/2Ha, AKR/Sn and RF/J), which were also nonresponsive to the induction of the metabolism of AFB1 to AFM1 (AFB1-4-hydroxylase activity), and Ah responsive strains (C57BL/6Ha, ICR/Ha, C3H/St, A/St, Balb/cCr, C57e/Ha and CBA/Pi), which were also responsive to the induction of AFB1-4-hydroxylase activity. The hepatic microsome-mediated enzyme activities studied included: mutagenic activation of AFB1 and benzo[a]pyrene in the Ames Salmonella typhimurium TA-98 system; metabolism of AFB1 and AFB2 to AFM1 and AFM2, respectively; and benzo[a]pyrene metabolism measured as the formation of fluorescent phenolic metabolites, i.e. aryl hydrocarbon hydroxylase (AHH) activity. Time-course and dose-response studies in C57BL/6Ha mice revealed that the metabolism of aflatoxin B1/B2 to aflatoxin M1/M2 (AFB1/B2-4-hydroxylase activity) was induced by both MC and beta NF. In the nonresponsive strains studied, pretreatment with MC or beta NF produced essentially little alteration of AFB1-4-hydroxylase activity or AHH activity or the mutagenic activation of AFB1 and benzo[a]pyrene. On the other hand, AFB1-4-hydroxylase activity in the responsive strains was induced 4- to 10-fold by MC (60 mg/kg) and 2.5- to 7-fold by beta NF (150 mg/kg). Also in the responsive strains, induction of AFB1-4-hydroxylase activity was strongly associated with (a) the depression of the mutagenic activation of AFB1, and (b) with the induction of both AHH and the mutagenic activation of benzo[a]pyrene. In summary, the results described in this report suggest that: (a) induction of AFB1-4-hydroxylase activity by MC (or beta NF) is associated with the depression of AFB1 mutagenesis and with the induction of benzo[a]pyrene mutagenesis; and (b) induction by MC (or beta NF) of AHH activity, AFB1-4-hydroxylase activity and AFB2-4-hydroxylase activity is controlled by either the same or closely linked genetic factors.
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PMID:Genetic expression of aflatoxin metabolism. Effects of 3-methylcholanthrene and beta-naphthoflavone on hepatic microsomal metabolism and mutagenic activation of aflatoxins. 631 70

Exposure of rats to 0.1 and 0.5 mg Cd/kg subcutaneously (s.c.) thrice weekly for 5 weeks resulted in an accumulation of cadmium in the liver in concentrations of 40 and 95 micrograms/g tissue, respectively, and a microsomal burden of Cd amounting to approx. 2-3% of the retained cadmium. The cytoplasm contained about 80% of the cadmium. At an exposure dose of 0.1 mg Cd/kg, stimulation of lipid peroxidation by 22% and inhibition of ALA synthetase by 16% in the liver were observed. The higher exposure of 0.5 mg Cd/kg caused an inhibition of microsomal monooxygenase with depression of cytochrome P-450 and cytochrome b5 by 20% (over 2-fold prolongation of hexobarbital sleeping time and statistically significant decrease of activity of aniline p-hydroxylase). The loss of cytochrome P-450 probably was due to an intensified lipid peroxidation and induction of heme oxygenase (30% and 60% over control, respectively). Sequestration of cadmium by cytoplasm (metallothionein) does not protect microsomes against cadmium accumulation and specific biochemical disturbances.
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PMID:Stimulation of lipid peroxidation and heme oxygenase activity with inhibition of cytochrome P-450 monooxygenase in the liver of rats repeatedly exposed to cadmium. 654 50

Adriamycin treatment in vivo or addition to incubation mixtures in vitro inhibits hepatic drug metabolism. It has been suggested that adriamycin-induced membrane lipid peroxidation may be a mechanism responsible for this activity in vitro. To determine if similar mechanisms operate in vivo, adriamycin inhibition of drug metabolism was compared in rats whose tissue lipid peroxidizability was altered by manipulating dietary levels of vitamin E. Weanling rats maintained on vitamin E deficient (0 ppm) or supplemented (10 or 100 ppm) diets for 12 weeks were given either adriamycin, 5 mg/kg/week, or equal volumes of the saline vehicle for 3 weeks intraperitoneally. Vitamin E deficiency alone (0 ppm, saline pretreatment) produced a 37% increase in hepatic lipid peroxidation without any appreciable alteration in hepatic aniline hydroxylase, ethylmorphine N-demethylase or aryl hydrocarbon hydroxylase activities. Adriamycin pretreatment altered hepatic lipid peroxidizability over corresponding saline pretreated controls dependent on dietary vitamin E. No increase was seen in the 100 ppm group, while 44% and 500% increases occurred at 10 and 0 ppm vitamin E, respectively. Adriamycin pretreatment decreased drug-metabolizing enzyme activity by an average of 32% for aniline hydroxylase, 26% for ethylmorphine N-demethylase and 63% for aryl hydrocarbon hydroxylase. Statistically, decreases in drug metabolism were independent of dietary vitamin E and did not correlate with lipid peroxidizability. These data would suggest that in vivo adriamycin-induced depression of hepatic drug-metabolizing enzymes is not mediated by elevated lipid peroxidation.
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PMID:Increasing lipid peroxidation by vitamin E deficiency does not augment adriamycin-induced inhibition of hepatic drug metabolism. 665 95

The effects of the PCBs mixture, Aroclor 1254, as modifiers of monooxygenases were studied in rabbits and mice. From data presented, it is not possible to generalize the biological effects of PCBs observed with rats, namely, that they are potent, nonspecific inducers of monooxygenase activities. This environmental pollutant enhanced microsomal drug-metabolizing enzymes in livers of rabbits and C57Bl/6J and DBA/2J mice. In rabbit lung, it inhibited, and in rabbit kidney, it enhanced the metabolism of ethylmorphine. Further, at dosages used, PCBs were poor inducers of aryl (benzo(a)pyrene) hydroxylase activity in livers of C57BL/6J and DBA/2J mice; they enhanced aryl hydrocarbon hydroxylase activity in rabbit kidney but caused a significant depression of its activity in rabbit lung. These studies demonstrate that the biologic impact of the widely distributed environmental pollutant, PCBs, may differ in different species and emphasize the need to carry out toxicological studies in more than one species of animals. The differential effects observed on various organs may also be important determinants of organ-targeted chemical toxicity.
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PMID:Polychlorinated biphenyls (PCBs) inducible monooxygenases in rabbits and mice: species and organ specificities. 680 95


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