Effect of glucose on induction of δ-aminolevulinic acid synthase, ferrochelatase and cytochrome P-450 hemoproteins in isolated rat hepatocytes by phenobarbital and lead

Cánepa, Eduardo T.; Llambías, Elena B.C.; Grinstein, Moisés

doi:10.1016/0304-4165(85)90020-0

Cited by 19 publications

(6 citation statements)

References 15 publications

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“…Increasing the levels of intracellular cyclic AMP can lead to an increase in total P-450 levels in isolated rat hepatocytes (Canepa et al, 1985). It is not clear, however, whether this effect is transcriptional and, indeed, the observed induction may very well be related to post-translational events, such as P-450 phosphorylation (Koch & Waxman, 1989;Pyerin & Taniguchi, 1989).…”

Section: Other Receptor-independent Induction Mechanismsmentioning

confidence: 98%

Phenobarbital induction of cytochrome P-450 gene expression

Waxman

Azaroff

1992

Biochemical Journal

496

265

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Section: Other Receptor-independent Induction Mechanismsmentioning

confidence: 98%

Phenobarbital induction of cytochrome P-450 gene expression

Waxman

Azaroff

1992

Biochemical Journal

496

265

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“…Hepatocytes were prepared according to the published method (Rumruen and Pool, 1984) (up to 4 h) employed (Canepa et al, 1985).…”

Section: Hepatocytesmentioning

confidence: 99%

Phosphorylation of hepatic phenobarbital-inducible cytochrome P-450.

Pyerin¹,

Taniguchi²

1989

The EMBO Journal

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The major phenobarbital-inducible cytochrome P450 purified from rat liver, a member of family II of the cytochrome P450 gene superfamily, is rapidly phosphorylated by cAMP-dependent protein kinase. The phosphorylation reaches > 0.5 mol phosphate/mol P450 after 5 min and is accompanied by a decrease in enzyme activity. The serine residue in position 128 was shown to be the sole phosphorylation site and a conformational change of the protein was indicated by a shift of the carbon monoxide difference spectrum of the reduced cytochrome from 450 to 420 nm. Comparison of amino acid sequences of various cytochrome P450 families revealed a highly conserved arginine residue in the immediate vicinity of the phosphorylated serine residue which constitutes the kinase recognition sequence. It also revealed that only the members of the cytochrome P450 family II carry this kinase recognition sequence. To find out whether this phosphorylation also occurs in vivo, the exchangeable phosphate pool of intact hepatocytes derived from phenobarbital-pretreated rats was labeled with 32P; followed by an incubation of the cells with the membrane-permeating dibutyryl-cAMP or with the adenylate cyclase stimulator glucagon to activate endogenous kinase. As a result, a microsomal polypeptide with the same electrophoretic mobility as cytochrome P450 became strongly labeled. Peptide mapping and immunoprecipitation with monospecific antibodies identified this protein as the major phenobarbitalinducible cytochrome P-450. It becomes phosphorylated at the same serine residues as in the cell-free phosphorylation. Since the degree of phosphorylation attained in hepatocytes is high enough to be of physiological significance, it is suggested that in liver cells and in liver tissue, phosphorylation may serve as an isoenzymespecific post-translational regulatory mechanism of cytochrome P450.

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“…This is well known to occur in patients suffering from acute porphyria (Doss et al, 1985;Moore and McColl, 1989;Kappas et al, 1995). Glucose-mediated repression of ALA synthase has been observed in whole rats as well as cultured hepatocytes (Giger and Meyer, 1981;DeLoskey and Beattie, 1984;Cánepa et al, 1984;Cánepa et al, 1985;Varone et al, 1996). The mechanism(s) controlling the glucose-mediated repression of ALA synthase has not been described, even as to whether regulation is transcriptional or post-transcriptional.…”

Section: Figmentioning

confidence: 94%

Effects of Modulators of Protein Phosphorylation on Heme Metabolism in Human Hepatic Cells: Induction ofδ-Aminolevulinic Synthase mRNA and Protein by Okadaic Acid

Cable

Kühn

Isom

2002

DNA and Cell Biology

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Effects of modulators of protein phosphorylation on delta-aminolevulinic acid (ALA) synthase and heme oxygenase-1 mRNA were analyzed in the human hepatic cell lines Huh-7 and HepG2 using a quantitative RNase protection assay. Okadaic acid was found to induce ALA synthase mRNA in a concentration-dependent fashion in both Huh-7 and HepG2 cells. The EC(50) for induction of ALA synthase mRNA in Huh-7 cells was 13.5 nM, with maximum increases occurring at okadaic acid concentrations of 25-50 nM. The EC(50) for induction of ALA synthase mRNA in HepG2 cells was 35.5 nM, with maximum increases occurring at okadaic acid concentrations of 50 nM. Concentration-dependent induction of ALA synthase mRNA paralleled the increase in ALA synthase protein. Maximum induction of ALA synthase was observed between 5 and 10 h post-treatment in both cell lines. Induction of ALA synthase mRNA in Huh-7 cells, but not HepG2 cells, was associated with an increase in ALA synthase mRNA stability. Okadaic acid also induced heme oxygenase-1 mRNA in both cell lines, but the magnitude of induction was only twofold, and was rapid and transient. Okadaic acid and phorbol 12-myristate 13-acetate significantly decreased heme-mediated induction of heme oxygenase-1 mRNA in both Huh-7 and HepG2 cells. Wortmannin diminished the heme-mediated induction of heme oxygenase-1 mRNA in HepG2 cells, but not Huh-7 cells. These results report a novel property of okadaic acid to affect heme metabolism in human cell lines.

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Effect of glucose on induction of δ-aminolevulinic acid synthase, ferrochelatase and cytochrome P-450 hemoproteins in isolated rat hepatocytes by phenobarbital and lead

Cited by 19 publications

References 15 publications

Phenobarbital induction of cytochrome P-450 gene expression

Phenobarbital induction of cytochrome P-450 gene expression

Phosphorylation of hepatic phenobarbital-inducible cytochrome P-450.

Effects of Modulators of Protein Phosphorylation on Heme Metabolism in Human Hepatic Cells: Induction ofδ-Aminolevulinic Synthase mRNA and Protein by Okadaic Acid

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