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)

A single acute dose of carbon disulfide (CS2, 5 mmol/kg ip) caused hepatic damage in rats pretreated with phenobarbital. Rats pretreated with phenobarbital and cobaltous chloride (CoCl2, 250 mumol/kg sc) were protected against CS2 induced hepatotoxicity. When single acute doses of CS2 and CoCl2 were given at the same time, however, rats developed a much more severe hepatic lesion than that seen following CS2 alone. Similar cotreatment of CoCl2 with bromobenzene, carbon tetrachloride or thioacetamide did not enhance the hepatotoxicity of these well-studied hepatotoxins. Additionally, other divalent metal salts (CuSO4 and ZnCl2) did not enhance CS2 hepatotoxicity. Hence, the interaction between CS2 and CoCl2 (that results in enhanced CS2 induced hepatic damage) appears to be relatively specific for these two agents. CS2 caused an approximate 50% decrease in hepatic cytochrome P-450 when given alone, but an approximate 85% decrease when given with CoCl2. This observation supports the hypothesis that the breakdown products of cytochrome P-450 heme are responsible for CS2 induced hepatotoxicity. In addition, single doses of CS2 or CoCl2 caused increases of 30 to 60% in hepatic glutathione (GSH), but additive responses were not obtained when the two agents were given at the same time. GSH synthetase and gamma-glutamyl transpeptidase activity were inconsistently changed by these treatments, and did not provide a consistent explanation for the increases in GSH. The enhanced hepatotoxicity of CS2 + CoCl2 is not due to changes in hepatic glutathione metabolism.
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PMID:Paradoxical effect of cobaltous chloride on carbon disulfide induced hepatotoxicity in rats. 317 44

Triiodothyronine administration to thyroidectomized animals, decreased cytochrome P-450 content by 50%. Haem oxygenase was not modified by triiodothyronine treatment, either alone or with a suboptimal dose of CoCl2. Under the same conditions hepatic delta-amino-laevulinic acid synthase activity was not affected. Triiodothyronine caused a two fold increase in tryptophan pyrrolase activity. Both the hole and total enzyme were increased to the same degree. Porphobilinogen deaminase-Uroporphyrinogen III Co-synthase activity was induced by 67% over thyroidectomized values, in triiodothyronine treated rats, and only 32% above the sham operated controls. Our results suggest that under triiodothyronine stimulation, the decrease in cytochrome P-450 content is not due to an enhanced rate of degradation of the haem moiety, but it rather dissociates to increase the cellular haem pool, and saturates in part the newly synthesized apotryptophan pyrrolase.
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PMID:Effect of triiodothyronine in the regulation of haem biosynthetic pathway. 327 26

Inhibitors of heme biosynthesis such as CoCl2, 3-amino-1,2,4-triazole, and thioacetamide block the 3-methylcholanthrene-mediated induction of cytochrome P-450 (c + d) messenger RNAs and their transcription in rat liver. This effect is specific, since the messenger RNA levels for albumin and glutathione transferase (Ya + Yc) and their transcription are not significantly influenced under conditions of heme depletion. Exogenous administration of heme at very low doses (50 micrograms/100 g body wt) is able to completely counteract the effects of the heme biosynthetic inhibitors on cytochrome P-450 (c + d) messenger RNA levels and their transcription. This constitutes a direct proof for the role of heme as a positive regulator of cytochrome P-450 gene transcription.
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PMID:Heme is a positive regulator of cytochrome P-450 gene transcription. 340 Oct 13

2-Allylisopropylacetamide, a porphyrinogen which decreases the microsomal and cytosolic heme pools, is a phenobarbitone-like inducer of cytochrome P-450(b + e) messenger RNAs in rat liver. The porphyrinogen, however, does not affect the nuclear heme pool and enhances the transcription of cytochrome P-450(b + e) messenger RNAs strikingly. Inhibitors of heme biosynthesis, such as CoCl2 and 3-amino-1,2,4-triazole, which decrease the total heme levels including that of the nuclear heme pool, block the 2-allylisopropylacetamide- or phenobarbitone-mediated increase in the transcription of cytochrome P-450(b + e) messenger RNAs. Administration of exogenous heme at a very low concentration (25 micrograms/100 g) is able to counteract the inhibitory effects of the heme biosynthetic inhibitors. Addition of heme in vitro to heme-depleted nuclei leads to a significant increase in the transcription rates for cytochrome P-450(b + e) messenger RNAs. 2-Allylisopropylacetamide, unlike phenobarbitone, fails to increase the levels of cytochrome P-450b protein at 12 h after the drug administration, although there is a striking increase in the messenger RNA levels. Under conditions of 2-allylisopropylacetamide treatment, the cytochrome P-450 messenger RNA is translated, but the newly synthesized apoprotein undergoes rapid degradation. It is concluded that heme is a positive modulator of cytochrome P-450 gene transcription and is also required to stabilize the freshly synthesized apoprotein.
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PMID:Regulation of cytochrome P-450 messenger RNA and apoprotein levels by heme. 368 Feb 82

The induction of cytochrome P-450 (c+d) messenger RNAs in rat liver by 3-methyl cholanthrene follows a biphasic pattern. Administration of cycloheximide blocks the induction of cytochrome P-450 (c+d) messenger RNAs by 3-methylcholanthrene as well as cytochrome P-450 (b+e) messenger RNAs by Phenobarbitone. Transcription of these messenger RNAs in isolated nuclei is also blocked by cycloheximide administration. Thus cycloheximide not only fails to mimic the superinduction effects reported in hepatoma cell cultures, but actually blocks the specific transcription process. Exogenous hemin, while counteracting the effects of CoCl2 (heme biosynthetic inhibitor) on cytochrome (c+d) messenger RNA induction by the hydrocarbon, fails to counteract the effects of cycloheximide. It is suggested that a positive labile transcription factor is involved in the regulation of cytochrome P-450 gene expression in vivo.
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PMID:Differential effects of cycloheximide on rat liver cytochrome P-450 gene transcription in the whole animal and hepatoma cell culture. 368 89

The metabolism of pargyline proceeds by way of three separate cytochrome P-450 catalyzed N-dealkylation reactions: N-depropargylation, N-demethylation and N-debenzylation. Propiolaldehyde, a product of N-depropargylation, is a potent inhibitor of aldehyde dehydrogenase (AlDH). The formation of pargyline-derived propiolaldehyde by isolated rat liver microsomes in vitro was confirmed using gas chromatographic/mass spectrometric techniques. The measured rates of propiolaldehyde formation for uninduced and phenobarbital-induced microsomes in vitro were 0.2 +/- 0.03 and 0.9 +/- 0.2 mumole/30 min/g wet weight liver respectively. However, these rates may have been artificially low due to competition between semicarbazide, the trapping agent, and microsomal proteins for the generated propiolaldehyde. CO significantly inhibited the microsome-catalyzed N-depropargylation reaction in vitro, whereas CoCl2 pretreatment of rats partially blocked the pargyline-induced rise in blood acetaldehyde after ethanol. Inhibition of the low Km liver mitochondrial AlDH by propiolaldehyde in vitro exhibited first-order kinetics, which is consistent with irreversible inhibition. Acetaldehyde did not attenuate the inhibition of AlDH by propiolaldehyde in vitro or by pargyline in vivo. Propargyl alcohol, a substance which is metabolized to propiolaldehyde by alcohol dehydrogenase, also inhibited AlDH in vivo and caused a quantitatively similar rise in blood acetaldehyde after ethanol as pargyline. Other putative metabolites of pargyline, namely benzylamine and propargylamine, inhibited AlDH in vivo, albeit to a lesser degree than pargyline, but neither of these amines inhibited AlDH directly. Monoamine oxidase was implicated in the conversion of benzylamine to an active inhibitory species, possibly an imine. From these studies, we conclude that propiolaldehyde was the primary metabolite responsible for the pargyline inhibition of AlDH in vivo; however, certain amine metabolites may have contributed to a lesser degree by conversion to yet unknown inhibitory forms.
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PMID:Role of propiolaldehyde and other metabolites in the pargyline inhibition of rat liver aldehyde dehydrogenase. 370 13

A cDNA clone for the Ya subunit of glutathione transferase from rat liver was constructed in E. coli. The clone hybridized to Ya and Yc subunit messenger RNAs. On the basis of experiments involving cell-free translation and hybridization to the cloned probe, it was shown that prototype inducers of cytochrome P-450 such as phenobarbitone and 3-methylcholanthrene as well as inhibitors such as CoCl2 and 3-amino-1,2,4-triazole enhanced the glutathione transferase (Ya+Yc) messenger RNA contents in rat liver. A comparative study with the induction of cytochrome P-450 (b+e) by phenobarbitone revealed that the drug manifested a striking increase in the nuclear pre-messenger RNAs for the cytochrome at 12 hr, but did not significantly affect the same in the case of glutathione transferase (Ya+Yc). 3-Amino-1,2,4-triazole and CoCl2 blocked the phenobarbitone mediated increase in cytochrome P-450 (b+e) nuclear pre-messenger RNAs. These compounds did not significantly affect the glutathione transferase (Ya+Yc) nuclear pre-messenger RNA levels. The polysomal, poly (A)- containing messenger RNAs for cytochrome P-450 (b+e) increased by 12-15 fold after phenobarbitone administration, reached a maximum around 16 hr and then decreased sharply. In comparison, the increase in the case a glutathione transferase (Ya+Yc) messenger RNAs was sluggish and steady and a value of 3-4 fold was reached around 24 hr. Run-off transcription rates for cytochrome P-450 (b+e) increased by nearly 15 fold in 4 hr after phenobarbitone administration, whereas the increase for glutathione transferase (Ya+Yc) was only 2.0 fold. At 12 hr after the drug administration, the glutathione transferase (Ya+Yc) transcription rates were near normal. Administration of 3-amino-1,2,4-triazole and CoCl2 blocked the phenobarbitone-mediated increase in the transcription of cytochrome P-450 (b+e) messenger RNAs. These compounds at best had only marginal effects on the transcription of glutathione transferase (Ya+Yc) messenger RNAs. The half-life of cytochrome P-450 (b+e) messenger RNA was estimated to be 3-4 hr, whereas that for glutathione transferase (Ya+Yc) was found to be 8-9 hr. Administration of phenobarbitone enhanced the half-life of glutathione transferase (Ya+Yc) messenger RNA by nearly two fold. It is suggested that while transcription activation may play a primary role in the induction of cytochrome P-450 (b+e), the induction of glutathione transferase (Ya+Yc) may essentially involve stabilization of the messenger RNAs.
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PMID:A comparative study of the regulation of cytochrome P-450 and glutathione transferase gene expression in rat liver. 375 27

The phenacetin breath test (PBT) has been proposed as an alternative to the aminopyrine breath test (ABT) for the assessment of hepatic function. To investigate the clinical utility of the PBT, we compared the PBT with the ABT in 9 healthy subjects and 18 patients with biopsy-proven liver disease. We also investigated the effects of cytochrome P-450 inducers in humans and rats, and the effect of cobaltous chloride (CoCl2) in rats on the PBT to elucidate the relationship between the rate of phenacetin deethylation and exhaled labeled CO2 derived from phenacetin. In humans with abnormal ABTs, the PBT correlated with the ABT (r = 0.77), but in healthy humans there was no correlation between the two breath tests. Rifampin pretreatment in healthy humans induced the ABT by 27%, but did not induce the PBT. In rats the PBT was not induced by 3-methylcholanthrene pretreatment at phenacetin doses of 1 mg per kg, but was induced by both 3-methylcholanthrene (178%) and phenobarbital (142%) at 10 mg per kg phenacetin. Pretreatment of rats with CoCl2, which reduces cytochrome P-450 content, decreased the PBT by 40% and the ABT by 84%. The insensitivity of the PBT to induction except at high doses of phenacetin suggests that phenacetin deethylation is not the rate-limiting process modulating exhaled labeled CO2 in healthy subjects, and that the PBT does not generally reflect normal or induced phenacetin dealkylation rates. The PBT, however, did reflect hepatic damage and may even be better than the ABT for grading the severity of hepatic damage.
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PMID:Comparison of the phenacetin and aminopyrine breath tests: effect of liver disease, inducers and cobaltous chloride. 392 Jan 35

In liver fractions from Sprague-Dawley rats, the metabolism of acrylonitrile (VCN) to cyanide (CN-) was localized the microsomal fraction and required NADPH and O2 for maximal activity. The biotransformation of VCN to CN- was characterized with respect to time, microsomal protein concentration, pH, and temperature. Metabolism of VCN was increased in microsomes obtained from phenobarbital-, Aroclor 1254-, or 3-methylcholanthrene-treated rats (479%, 414%, and 142% of control, respectively) and decreased with CoCl2 treatment (54% of control). The KM estimated for VCN with the phenobarbital (54.8 +/- 9.5 mM) or Aroclor 1254 (40.9 +/- 4.1 mM) preparation was lower than the control (190.7 +/- 19.7 mM). Addition of SKF 525-A or CO to incubation mixtures inhibited VCN metabolism. Addition of the epoxide hydratase inhibitor, 1,1,1-trichloropropane 2,3-oxide, decreased the formation of CN- from VCN. Addition of glutathione, cysteine, D-penicillamine, or 2-mercaptoethanol enhanced the release of CN- from VCN. These findings indicate that VCN is metabolized to CN- via a cytochrome P-450-dependent mixed-function oxidase system.
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PMID:Metabolism of acrylonitrile to cyanide. In vitro studies. 610 3

The kinetics of 14CO2 production in rats were investigated after oral, ip, or iv administration of 14C-aminopyrine (AP) at several dose levels, and after pretreatment with phenobarbital (PB) or partial hepatectomy to produce alterations in hepatic function. Several kinetic parameters were assessed with each route of administration and at each dose level (0.1, 10, and 50 mg/kg). The parameters found most useful were: time to reach peak, peak rate, 14CO2 production per min at 20 or 30 min expressed as percentage of total administered 14C (R20 or R30), and half-life of the decline in 14CO2 production after peak. It was found that the R30 value after oral administration or R20 after the ip administration of AP (10 mg/kg) reflected alterations in hepatic function without significant overlap of values. The use of the R20 or R30 parameters determined from a single collection was further assessed in control and in PB- and CoCl2-pretreated animals and found to be capable of distinguishing between these different groups of animals. In addition, the AP breath test (ABT) kinetics were not significantly affected by 3-methylcholanthrene pretreatment. In another set of experiments, R30 values determined in controls and in PB- and CoCl2-pretreated rats demonstrated excellent correlation to changes in hepatic microsomal AP and ethylmorphine N-demethylase and aniline hydroxylase activities and cytochrome P-450 content. similar correlations were obtained with R20 after the ip administration of 10 mg of AP per kg. These findings indicate that the ABT is capable of accurately assessing AP N-demethylase activity and other parameters of hepatic mono-oxygenase activity.
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PMID:The in vivo measurement of expired 14CO2 derived from the N-demethylation of aminopyrine as a reflection of the in vitro hepatic cytochrome P-450 drug-metabolism activity in rats. 612 58


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