Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D03574 (CoCl2)
 1,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

gamma-Hexachlorocyclohexane (gamma-HCH) was metabolized by dehydrochlorination, dehydrogenation and dechlorination in rat liver microsomes and these initial metabolites of gamma-HCH were identified as gamma-pentachlorocyclohexene (gamma-PCCH), gamma-hexachlorocyclohexene (gamma-HCCH) and gamma-tetrachlorocyclohexene (gamma-TCCH) by gas chromatography-mass spectrometry (GC/MS). The dehydrochlorination and dehydrogenation were performed in incubation media containing NADPH and p,p'-tetramethyldiaminodiphenyl methane (TPD, 30 nmol) which is known to inhibit the degradation of initial metabolites formed during an aerobic incubation of gamma-HCH with microsomes at 25 degrees C. The dechlorination was found to proceed well under anaerobic conditions. The dehydrogenation was inhibited by SKF 525-A, CO, piperonyl butoxide, N2 and the absence of NADPH, but not by cyanide. Additionally, pretreatment of rats with phenobarbital (PB), but not with 3-methylcholanthrene (3-MC), induced the dehydrogenation of gamma-HCH. These results suggest that cytochrome P-450 is involved in this reaction. The cytochrome b5 system may not be involved. The dehydrochlorination was inhibited by N2, CO, piperonyl butoxide, KCN and the absence of NADPH, but not by SKF 525-A. This reaction was enhanced by pretreatment of rats with SKF 525-A, CoCl2 and piperonyl butoxide. Pretreatment with PB and 3-MC did not show a significant effect on the dehydrochlorination activity. Thus, the results suggest that the dehydrochlorination could be catalyzed by a specific species of cytochrome P-450 and cytochrome b5 system and/or other microsomal enzyme systems.
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PMID:Initial metabolism of gamma-hexachlorocyclohexane (gamma-HCH) by rat liver microsomes. 619 4

In order to elucidate the enzymic basis of nitrosamine metabolism, the in vitro metabolism of nitrosamines by rat liver microsomes and the effects of fasting on the microsomal enzymes have been studied. Fasting for 1 to 3 days causes a 2- to 3-fold enhancement of the reduced nicotinamide adenine dinucleotide phosphate-dependent nitrosodimethylamine demethylase (NDMAD) activity. The cytochrome P-450 content and the activities of reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase and benzphetamine demethylase, however, are only modestly increased. Gel electrophoretic analysis reveals the induction of a 50,000-dalton protein band during fasting. The induction of this protein band as well as the enhancement of NDMAD activity are inhibited by CoCl2 and inhibitors of protein and RNA biosynthesis. The involvement of cytochrome P-450 in the NDMAD is supported by the fact that microsomal reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase is required for the demethylase activity. Kinetic analysis indicates that a low-Km form of NDMAD (apparent Km, 0.07 mM) is markedly induced by fasting. With microsomes of control rats, there are at least three apparent Km values (0.07, 0.38, and 38.6 mM) for NDMAD; but with microsomes of fasting rats, the low-Km (0.07 mM) form is predominant. These results suggest that rat liver microsomes contain a cytochrome P-450 isozyme which has high affinity for nitrosodimethylamine, and this isozyme is induced by fasting. In addition to nitrosodimethylamine, the oxidative demethylation of N-nitroso-N-methylethylamine, N-nitroso-N-methylbutylamine, N-nitroso-N-methylaniline, and N-nitroso-N-methylbenzylamine is also enhanced by fasting. The extent of enhancement and substrate dependency of these reactions, however, is different from that of NDMAD.
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PMID:High-affinity nitrosamine dealkylase system in rat liver microsomes and its induction by fasting. 640 Dec 21

The effects of acetone and isopropanol on the microsomal monooxygenase system have been investigated to study the role of this enzyme system in the metabolism of nitrosamines. Treatment of rats with acetone or isopropanol (2.5-5 ml/kg, i.g.) causes a 3-4.5-fold enhancement in the NADPH-dependent nitrosodimethylamine demethylase (NDMAd) activity. This is accompanied by only moderate increases in the gross cytochrome P-450 (P-450) content and NADPH-cytochrome c reductase activity. Several other monooxygenase activities were increased to different extents from an 8% increase in aryl hydrocarbon hydroxylase to a 261% increase in ethoxycoumarin O-dealkylase activities. Kinetic analysis indicates that a low Km form of NDMAd (Km = 0.07 mM) is induced by these treatments. In the microsomes of the treated rats, this high affinity form becomes predominant, in contrast to control microsomes which possess at least three Km-values for NDMAd. The treatment also enhances the metabolism of nitrosomethylethylamine, nitrosomethylbenzylamine and nitrosomethylaniline although to lesser extents than with nitrosodimethylamine. Several lines of observations suggest that the enhanced NDMAd is due to the induction of one or more specific P-450 isozyme(s) by pretreatment with acetone or isopropanol: (a) The treatment induces proteins with molecular weights (Mr) of 50 000 and 52 000 which are in the range of known P-450 isozymes. (b) The induction of these proteins and NDMAd activity was inhibited by CoCl2 and cycloheximide. (c) The induced microsomes had a peak at 450.6 nm different from the 450.0 nm peak of control microsomes. When added to the incubation mixture, both acetone and isopropanol inhibit NDMAd activity. Isopropanol is more potent than acetone and is shown to be a competitive inhibitor with a Ki-value of 0.151 mM.
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PMID:Induction of a high affinity nitrosamine demethylase in rat liver microsomes by acetone and isopropanol. 640 34

Troleandomycin, a macrolide antibiotic, has been shown to be demethylated and oxidized into a metabolite which forms an inactive complex with the iron(II) of cytochrome P-450. The role of glutathione in the metabolism of troleandomycin was investigated. Administration of troleandomycin (1 mmol X kg-1 p.o.) decreased the concentration of glutathione in the liver. The depletion of glutathione was increased in rats pretreated with phenobarbital and decreased in rats pretreated with CoCl2. In vitro, an inverse relationship was found between the concentration of glutathione in the incubation mixture and the appearance of the cytochrome P-450-troleandomycin metabolite complex. Glutathione, however, did not inhibit the demethylation of troleandomycin and did not destroy the cytochrome P-450-troleandomycin metabolite complex. The in vitro protective effect of glutathione was reproduced by cysteine but not by glycine. In vivo, decreasing the concentration of glutathione in the liver by food deprivation or by the administration of diethylmaleate increased the formation of the cytochrome P-450-troleandomycin metabolite complex. These results indicate that glutathione is depleted by a troleandomycin metabolite in vivo, whereas glutathione protects against the formation of the inactive cytochrome P-450-troleandomycin metabolite complex in vitro and in vivo.
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PMID:Inactivation of cytochrome P-450 by a troleandomycin metabolite. Protective role of glutathione. 660 Jul 90

Diabetes-induced alterations in heme and hemoproteins, as well as its relationship to drug-mediated induction of ALA Synthase (ALA-S), were examined in female Sprague-Dawley rats. Animals were rendered diabetic by a single i.v. injection of streptozotocin (STZ, 65 mg/kg) and measurements were made at various times after treatment. The basal levels of the key enzymes involved in heme synthesis, ALA-S and ALA-dehydratase (ALA-D), were decreased about 36% and 54%, respectively, 44-46 days after diabetes induction. Furthermore, the catabolism of heme that occurs via microsomal heme oxygenase progressively decreases in activity during the course of diabetes, and reaches 69% of control in 90-day diabetic animals. The basal levels of heme, cytochromes P-450 and b5 were elevated about twofold in diabetic rats as compared with their corresponding control values. The activity of benzo(a)pyrene hydroxylase in diabetic rats was also increased in proportion to the microsomal content of cytochrome P-450. In contrast, delta 4-hydrogenase, the rate-limiting enzyme in corticosterone metabolism, exhibited a 35-65% decrease in activity throughout the experimental period. Tryptophan pyrrolase activity (total, holo-, and apoenzyme) was elevated about 2.5-fold in STZ diabetic rats. In vivo insulin therapy of diabetic animals antagonized the effect of the diabetic state on the above measured parameters. Treatment with aminoglutethimide resulted in about a twofold elevation in ALA-S activity in control as well as chronically diabetic rats. However, a similar stimulatory response in ALA-S activity to CoCl2 administration was observed only in control or insulin-treated diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Diabetes-induced metabolic alterations in heme synthesis and degradation and various heme-containing enzymes in female rats. 660 90

Concurrent treatments of cobalt chloride (CoCl2) and phenobarbital (PB), alone or in combination with lithocholic acid (LCA), were administered to rats for 7 days to assess whether or not a hypoactive hypertrophic smooth endoplasmic reticulum (HHSER) could be induced, as well as investigating the potential role of HHSER in the pathogenesis of cholestasis. LCA given alone slightly reduced hepatic triglycerides, significantly elevated plasma triglycerides and decreased microsomal glucose-6-phosphatase (G6P-ase) activity. PB administered alone significantly increased hepatic phospholipids and microsomal protein, phospholipid and cytochrome P-450 contents, as well as microsomal aminopyrine-N-demethylase (APDM-ase) activity. Functional indicators of liver impairment were associated primarily with CoCl2 treatment, whether given alone or in combination with PB + LCA. These signs included significantly reduced hepatic triglycerides, and increased plasma triglycerides associated with enhanced release of hepatic VLDL-triglycerides, as well as significantly decreased microsomal G6P-ase activity and/or reduced APDM-ase activity and cytochrome P-450 content. Elevated plasma bilirubin levels, and aspartate and alanine aminotransferase activities were also evident with concurrent CoCl2 + PB + LCA treatments. Combined CoCl2 + PB treatments, with or without LCA, caused significant increases in microsomal protein and phospholipid, and decreased activity of the rough endoplasmic reticulum (RER) marker G6P-ase, but no changes in cytochrome P-450 levels and no marked alterations in the activity of the SER marker APDM-ase. The data indicated that simultaneous CoCl2 and PB treatments, whether given alone or in combination with LCA, caused a functional impairment of the RER, and did not induce HHSER membranes.
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PMID:Functional responses of the rat hepatic endoplasmic reticulum to treatment proposed as a model for cholestasis. 668 66

Pretreatment of rats with cobaltous chloride has been shown previously to reduce the content of cytochrome P-450 in the hepatic microsomal protein. This is accompanied by a corresponding decrease in substrate oxidation, e.g. ethyl morphine demethylation, in vitro. The present paper shows that pretreatment of C57BL/6J Han mice with 40 mg of CoCl2/kg/day for 2 days results in a decrease of cytochrome P-450 to 60% of its original value. This is accompanied by a corresponding decrease in overall rate of [14C]methacetin demethylation as measured by 14CO2 exhalation. However, when 7-[methoxy-14C]coumarin is the substrate, cobalt-pretreated animals exhale twice as much 14CO2 than normal animals. Considering the decrease in cytochrome P-450 (and assuming linear relationship between metabolic activity and cytochrome P-450 content), this observation suggested a 2.5-fold increase in the specific activity of the remaining cytochrome P-450. This was found to be true in vitro. It is concluded that cobalt pretreatment of mice leads to an enhanced in vivo demethylation rate of 7-[methoxy-14C]coumarin which is explained by a considerably higher molecular monooxygenase activity toward this substrate that is found in vitro.
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PMID:Acceleration of 7-[methoxy-14C]coumarin-derived carbon dioxide exhalation by cobalt pretreatment in mice. 680 66

The induction of hepatic heme oxygenase in response to cobaltous chloride (CoCl2) administration was examined in normal, sham-operated, and adrenalectomized rats. The basal level of heme oxygenase was elevated about 2-fold in adrenalectomized rats as compared to normal controls or sham-operated animals. The extent of heme oxygenase induction by CoCl2 was also increased about 2-fold above normal in adrenalectomized animals and was accompanied by an enhanced breakdown of cytochrome P-450. The initial decline (approximately 2 h) and the late rebound increase (approximately 16 h) of delta-aminolevulinate synthase activity caused by the metal administration were, however, similar for all three groups of animals. Hydrocortisone is known to restore the impaired inducibility of delta-aminolevulinate synthase by allylisopropylacetamide in adrenalectomized rats. In this study, treatment with hydrocortisone prevented the exaggerated metal induction of heme oxygenase but did not affect the associated initial decline or the late rebound of delta-aminolevulinate synthase. These data indicate that hydrocortisone and adrenalectomy can significantly influence the extent of the induction of heme oxygenase produced by CoCl2, but that both the initial decline and the rebound induction of delta-aminolevulinate synthase associated with this metal treatment are apparently independent of these endocrine controls.
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PMID:Adrenalectomy enhances the induction of heme oxygenase and the degradation of cytochrome P-450 in liver. 689 9

The relation between the delta-aminolevulinate-synthase and heme-oxygenase activities and the contents of cytochromes b5 and P-450 in rat liver after phenobarbital and CoCl2 injections was studied. Two hours after a single injection of phenobarbital the delta-aminolevulinate-synthase activity is increased, showing a further rise after 24 hrs. The content of cytochrome b5 is not changed, while that of cytochrome P-450 is increased 24 hrs after the injection. The heme-oxygenase activity remains unaffected thereby. The increase in the enzyme activity and cytochrome P-450 content induced by phenobarbital is eliminated by a preliminary administration of actinomycin D. The administration of CoCl2 is accompanied by a decrease in the delta-aminolevulinate-synthase activity after 2 hrs and its further increase after 24 hrs. The heme-oxygenase activity shows a sharp rise 24 hrs after the injection. The rise in the delta-aminolevulinate-synthase activity induced by CoCl2 is removed by actinomycin D. CoCl2 decreases the content of cytochromes b5 and P-450 24 hrs after the injection. It is assumed that the correlation between the delta-aminolevulinate-synthase activity and cytochrome P-450 content is observed only in the case when the heme-oxygenase activity is not increased. The cytochrome b5 content is independent of the changes in the activity of the key enzyme of heme synthesis and depends to a certain extent on the rate of heme degradation by heme-oxygenase.
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PMID:[Activity of key enzymes of heme synthesis and degradation and contents of cytochromes b5 and P-450 in rat liver]. 689 39

The responses of hepatic delta-aminolaevulinate synthase and microsomal haem oxygenase to inducers were examined in pregnant rats. 2-Allyl-2-isopropylacetamide-mediated induction of delta-aminolaevulinate synthase was greatly decreased during pregnancy and in the early post-partum period. Administration of allylisopropylacetamide to pseudopregnant rats induced delta-aminolaevulinate synthase normally. Treatment of pregnant rats with cortisol failed to restore the drug-mediated induction of delta-aminolaevulinate synthase. Microsomal cytochrome P-450 content and the activities of drug-metabolizing enzymes such as aniline hydroxylase and ethylmorphine. N-demethylase were significantly lowered during pregnancy. In contrast with the greatly impaired induction of delta-aminolaevulinate synthase, the induction of haem oxygenase in response to CoCl2 remained unaltered in pregnant rats. The normal perturbations of delta-aminolaevulinate synthase, consisting of an initial inhibition followed by a rebound increase in the enzyme activity associated with CoCL2 treatment, were observed during pregnancy. These findings indicate that hormones and metabolic factors associated with gestation exert significant but differential controls on the induction patterns of delta-aminolaevulinate synthase and haem oxygenase.
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PMID:Differential responses to inducers of delta-aminolaevulinate synthase and haem oxygenase during pregnancy. 689 93


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