Literature DB >> 486136

Inhibition by cycloheximide of degradation of cytochrome P-450 in primary cultures of adult rat liver parenchymal cells and in vivo.

P S Guzelian, J L Barwick.   

Abstract

Degradation of cytochrome P-450 was studied in adult rat liver parenchymal cells in primary monolayer culture. In cells incubated in standard culture medium, the amount of cytochrome P-450 decreased at an accelerated rate relative to either the rate of degradation of total protein in the cells or the turnover of cytochrome P-450 in vivo. This change was succeeded by a spontaneous increase in the activity of haem oxygenase, an enzyme system that converts haem into bilirubin in vitro, measured in extracts from the cultured cells. This finding suggests that the rate of cytochrome P-450 breakdown may be controlled by factor(s) other than the activity of haem oxygenase. The decline in cytochrome P-450 and the subsequent increase in haem oxygenase activity was prevented by incubation of hepatocytes in medium containing an inhibitor of protein synthesis such as cycloheximide, puromycin, actinomycin D, or azaserine. The effect of cycloheximide appeared to be due to decreased breakdown of microsomal (14)C-labelled haem. By contrast, cycloheximide was without effect on the degradation of total protein, measured either in homogenates or in microsomal fractions prepared from the cultured cells. These results suggest that the conditions of cell culture stimulate selective degradation of cytochrome P-450 by a process that is inhibited by cycloheximide and hence may require protein synthesis. The findings in culture were verified in parallel studies of cytochrome P-450 degradation in vivo. After administration of bromobenzene, the degradation of the haem moiety of cytochrome P-450 was accelerated in vivo in a manner resembling that observed in cultured hepatocytes. Administration of cycloheximide to either bromobenzene-treated rats or to untreated rats decreased the degradation of the haem moiety of cytochrome P-450. However, the drug failed to affect degradation of haem not associated with cytochrome P-450, suggesting that cycloheximide is not a general inhibitor of haem oxidation in the liver. These findings confirm that the catabolism of hepatic cytochrome P-450 haem is controlled by similar cycloheximide-sensitive processes in the basal steady state in vivo, as stimulated by bromobenzene in vivo, or in hepatocytes under the conditions of cell culture. We conclude that the rate-limiting step in this process appears to require protein synthesis and precedes cleavage of the haem ring.

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Year:  1979        PMID: 486136      PMCID: PMC1161102          DOI: 10.1042/bj1800621

Source DB:  PubMed          Journal:  Biochem J        ISSN: 0264-6021            Impact factor:   3.857


  47 in total

1.  Regulation of tyrosine transaminase degradation in the isolated perfused rat liver by cycloheximide and insulin.

Authors:  P O Seglen
Journal:  Biochim Biophys Acta       Date:  1971-02-23

2.  Control of degradation and synthesis of induced tyrosine aminotransferase studied in hepatoma cells in culture.

Authors:  F Auricchio; D Martin; G Tompkins
Journal:  Nature       Date:  1969-11-22       Impact factor: 49.962

3.  Microsomal heme oxygenase. Characterization of the enzyme.

Authors:  R Tenhunen; H S Marver; R Schmid
Journal:  J Biol Chem       Date:  1969-12-10       Impact factor: 5.157

4.  Regulation of tyrosine transaminase in the isolated perfused rat liver.

Authors:  I B Levitan; T E Webb
Journal:  J Biol Chem       Date:  1969-09-10       Impact factor: 5.157

5.  Ascorbic acid and drug metabolism.

Authors:  V G Zannoni; E J Flynn; M Lynch
Journal:  Biochem Pharmacol       Date:  1972-05-15       Impact factor: 5.858

6.  Compartmentation of free valine and its relation to protein turnover in perfused rat liver.

Authors:  G E Mortimore; K H Woodside; J E Henry
Journal:  J Biol Chem       Date:  1972-05-10       Impact factor: 5.157

7.  The influence of phenobarbital on the turnover of hepatic microsomal cytochrome b5 and cytochrome P-450 hemes in the rat.

Authors:  H Greim; J B Schenkman; M Klotzbücher; H Remmer
Journal:  Biochim Biophys Acta       Date:  1970-01-27

8.  Chemically induced porphyria: increased microsomal heme turnover after treatment with allylisopropylacetamide.

Authors:  U A Meyer; H S Marver
Journal:  Science       Date:  1971-01-08       Impact factor: 47.728

9.  Protein turnover in skeletal muscle. II. The effect of starvation and a protein-free diet on the synthesis and catabolism of skeletal muscle proteins in comparison to liver.

Authors:  D J Millward
Journal:  Clin Sci       Date:  1970-11       Impact factor: 6.124

10.  Biphasic decrease of radioactive hemoprotein from liver microsomal CO-binding particles. Effect of 3-methylcholanthrene.

Authors:  W Levin; R Kuntzman
Journal:  J Biol Chem       Date:  1969-07-10       Impact factor: 5.157

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  3 in total

Review 1.  Use of hepatocytes in primary culture for biochemical studies on liver functions.

Authors:  A Ichihara; T Nakamura; K Tanaka
Journal:  Mol Cell Biochem       Date:  1982-04-02       Impact factor: 3.396

2.  Evidence that ligand formation is a mechanism underlying the maintenance of cytochrome P-450 in rat liver cell culture. Potent maintenance by metyrapone.

Authors:  A J Paine; P Villa; L J Hockin
Journal:  Biochem J       Date:  1980-06-15       Impact factor: 3.857

3.  Degradation of cytochrome P-450 haem by carbon tetrachloride and 2-allyl-2-isopropylacetamide in rat liver in vivo and in vitro. Involvement of non-carbon monoxide-forming mechanisms.

Authors:  P S Guzelian; R W Swisher
Journal:  Biochem J       Date:  1979-12-15       Impact factor: 3.857

  3 in total

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