scholarly journals Control of δ-aminolaevulinate synthase and haem oxygenase in chroniciron-overloaded rats

1981 ◽  
Vol 200 (1) ◽  
pp. 35-42 ◽  
Author(s):  
N G Ibrahim ◽  
J C Nelson ◽  
R D Levere
Keyword(s):  
Iron Overload ◽  
Inborn Errors ◽  
Cellular Iron ◽  
Drug Metabolizing Enzyme ◽  
Oxygenase Activity ◽  
Exogenous Agents ◽  
Haem Oxygenase ◽  
Metabolizing Enzyme ◽  
Cytochrome P 450

The hepatic porphyrias are inborn errors of porphyrin and haem biosynthesis characterized biochemically by excessive excretion of delta-aminolaevulinate (ALA), porphobilinogen and other intermediates in haem synthesis. Clinical evidence has implicated iron in the pathogenesis of several types of genetically transmitted diseases. We investigated the role of iron in haem metabolism as well as its relationship to drug-mediated induction of ALA synthase and haem oxygenase in acute and chronic iron overload. Acute iron overload in rats resulted in a marked increase in hepatic haem oxygenase that was associated with a decrease in cytochrome P-450 and an increase in ALA synthase activity. Aminopyrine N-demethylase and aniline hydroxylase activities, which are dependent on the concentration of cytochrome P-450, were also decreased. In contrast, in chronic-iron-overloaded rats, there was an adaptive increase in haem oxygenase activity and an increase in ALA synthase that was associated with normal concentrations of microsomal haem and cytochrome P-450. The induction of ALA synthase in chronic iron overload was enhanced by phenobarbital and allylisopropylacetamide, in spite of the fact that these agents did not increase haem oxygenase activity. Small doses of Co2+ were potent inducers of the haem oxygenase in chronic-iron-overloaded, but not in control, animals. We conclude that increased hepatic cellular iron may predispose certain enzymes of haem synthesis to induction by exogenous agents and thereby affect drug-metabolizing enzyme activities.

scholarly journals The role of cytochrome P-450 in cholesterol biogenesis and catabolism

1972 ◽  
Vol 128 (2) ◽  
pp. 237-242 ◽  
Author(s):  
Sandra D. Atkin ◽  
Eileen D. Palmer ◽  
P. D. English ◽  
B. Morgan ◽  
M. A. Cawthorne ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Carbon Disulphide ◽  
Normal Serum ◽  
Liver Cholesterol ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Cytochrome P 450

1. Adjuvant-induced arthritis in rats is accompanied by a loss of activity of the drug-metabolizing enzyme system and a decrease in hepatic cytochrome P-450. 2. Arthritic rats have normal serum and liver cholesterol concentrations. 3. The rate of biogenesis of cholesterol in vivo and in vitro from either [14C]acetate or [14C]mevalonate in arthritic rats was the same as or greater than that found in control rats. 4. Treatment of rats with carbon disulphide (1ml/kg) resulted in a loss of drug-metabolizing-enzyme activity and increased cholesterol biogenesis. 5. The activity of cholesterol 7α-hydroxylase in adjuvant-induced arthritic rats did not differ significantly from that in control rats. 6. Rats fed with cholestyramine had an elevated hepatic cholesterol 7α-hydroxylase activity, but neither the concentration of cytochrome P-450 nor the activity of the drug-hydroxylating enzyme, aminopyrine demethylase, was affected. 7. The relationships between drug hydroxylation and cholesterol metabolism are discussed.

scholarly journals Regulation of hepatic haem metabolism. Disparate mechanisms of induction of haem oxygenase by drugs and metals

1988 ◽  
Vol 250 (1) ◽  
pp. 189-196 ◽  
Author(s):  
B C Lincoln ◽  
J F Healey ◽  
H L Bonkovsky
Keyword(s):  
Chick Embryo ◽  
Primary Culture ◽  
In Ovo ◽  
Oxygenase Activity ◽  
Haem Oxygenase ◽  
Cytochrome P 450

We studied drug- and metal-mediated increases in activity of haem oxygenase, the rate-controlling enzyme for haem breakdown, in chick-embryo hepatocytes in ovo and in primary culture. Phenobarbitone and phenobarbitone-like drugs (glutethimide, mephenytoin), which are known to increase concentrations of an isoform of cytochrome P-450 in chick-embryo hepatocytes, were found to increase activities of haem oxygenase as well. In contrast, 20-methylcholanthrene, which increases the concentration of a different isoform of cytochrome P-450, had no effect on activity of haem oxygenase. Inhibitors of haem synthesis, 4,6-dioxoheptanoic acid or desferrioxamine, prevented drug-mediated induction of both cytochrome P-450 and haem oxygenase in embryo hepatocytes in ovo or in culture. Addition of haem restored induction of both enzymes. These results are interpreted to indicate that phenobarbitone and its congeners induce haem oxygenase by increasing hepatic haem formation. In contrast, increases in haem oxygenase activity by metals such as cobalt, cadmium and iron were not dependent on increased haem synthesis and were not inhibited by 4,6-dioxoheptanoic acid. We conclude that (1) induction of hepatic haem oxygenase activity by phenobarbitone-type drugs is due to increased haem formation, and (2) induction of haem oxygenase by drugs and metals occurs by different mechanisms.

Effect of Splenectomy on the Activity of Drug-Metabolizing Enzymes in the Liver of Rats

1971 ◽  
Vol 49 (3) ◽  
pp. 161-166 ◽  
Author(s):  
Jules Brodeur ◽  
Claude Marchand
Keyword(s):  
Indirect Evidence ◽  
Female Rats ◽  
Microsomal Enzymes ◽  
Drug Metabolizing Enzyme ◽  
Effect Of Splenectomy ◽  
Maximal Induction ◽  
Metabolizing Enzyme ◽  
Cytochrome P 450 ◽  
Liver Microsomal Enzymes

Splenectomy was performed in adult female rats in order to investigate the influence of removal of the spleen on liver microsomal enzymes and cytochrome P-450 in vitro, as well as on the pharmacological activity of certain drugs in intact animals. Splenectomy significantly decreases the amount of cytochrome P-450 at 1 and 4 days after the operation, but not at 7 days. The activity of the enzymes catalyzing the metabolism of parathion, p-nitroanisole, and zoxazolamine is also decreased 4 days after splenectomy, whereas that of the enzymes involved in the metabolism of hexobarbital is unchanged. The maximal induction by phenobarbital of the enzymatic activities catalyzing the metabolism of parathion, p-nitroanisole, and zoxazolamine is prevented by splenectomy. Splenectomy exerts very little effect on plasma levels of hexobarbital and hexobarbital sleeping time; however, in both control and phenobarbital-pretreated rats, splenectomy results in a marked increase in the duration of zoxazolamine paralysis. These results indicate that splenectomy exerts inhibitory effects on certain liver microsomal enzymes, and provide some indirect evidence in support of the view that the hepatic blood supply is important for maintaining normal levels of drug-metabolizing enzyme activity in the liver.

scholarly journals Accelerated hepatic haem catabolism in the selenium-deficient rat

1977 ◽  
Vol 168 (1) ◽  
pp. 105-111 ◽  
Author(s):  
R F Burk ◽  
M A Correia
Keyword(s):  
Urinary Excretion ◽  
Sodium Dodecyl Sulphate ◽  
Gel Electrophoresis ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Fold Increase ◽  
Microsomal Cytochrome ◽  
Haem Oxygenase ◽  
Cytochrome P 450

1. Hepatic microsomal cytochrome P-450 concentrations are lower in selenium-deficient rats treated with phenobarbital for 4 days than in similarly treated control rats. 2. No defect in haem synthesis was found on the basis of measurements of delta-aminolaevulinate synthase (EC 2.3.1.37), delta-aminolaevulinate dehydratase (EC 4.2.1.24) and ferrochelatase (EC 4.99.1.1) activities, and urinary excretion of delta-aminolaevulinate, porphobilinogen, uroporphyrin and coproporphyrin. 3. No defect in apo-(cytochrome P-450) separated by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. 4. An increase in haem catabolism was found. An 8-fold increase in hepatic microsomal haem oxygenase (EC 1.14.99.3) activity occurred in selenium-deficient rats after phenobarbital treatment, compared with a less than 2-fold increase in control rats. Also excretion of 14CO in the breath after administration of delta-amino[5-14C]laevulinate was greater by phenobarbital-treated selenium-deficient rats than by similarly treated controls. 5. These studies demonstrate that the defective induction of cytochrome P-450 by phenobarbital in selenium-deficient rats is accompanied by increased haem catabolism. This could be due to increased breakdown of cytochrome P-450 or to catabolism of haem before it attaches to the apo-cytochrome. The role of selenium in stabilizing cytochrome P-450 and/or in protecting haem from breakdown remains to be determined.

scholarly journals The role of nitric oxide on decreasing the hepatic drug metabolizing enzyme activity by bacterial endotoxin in rats

1999 ◽  
Vol 79 ◽  
pp. 125
Author(s):  
Kiyoyuki Kitaichi ◽  
Li Wang ◽  
Haruna Kidokoro ◽  
Mitsunori Iwase ◽  
Kenji Takagi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Enzyme Activity ◽  
Bacterial Endotoxin ◽  
Hepatic Drug ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme

Binding of anticonvulsant drugs to cytochrome P-450: correlation with evidence of induction of hepatic microsomal enzymes

1976 ◽  
Vol 54 (6) ◽  
pp. 844-849 ◽  
Author(s):  
A. N. Latham ◽  
G. D. Sweeney
Keyword(s):  
Glucaric Acid ◽  
Binding Characteristics ◽  
Drug Metabolizing Enzyme ◽  
Close Relationship ◽  
Dependent Inhibition ◽  
Metabolizing Enzyme ◽  
Cytochrome P 450 ◽  
Hepatic Microsomal Enzymes ◽  
Binding Behaviour

Mephenytoin, diphenylhydantoin, pheneturide, and phenobarbital produced a concentration-dependent inhibition in the binding of hexobarbital to cytochrome P-450 at the type 1 site, while sulthiame slightly potentiated, and ethosuximide did not affect the binding characteristics of hexobarbital. Diphenylhydantoin, phenobarbital, and pheneturide have previously been shown to enhance the urinary excretion of D-glucaric acid (DGA), while sulthiame inhibited the potentiation of DGA excretion caused by these drugs, and ethosuximide produced no change. The results suggest a close relationship between the ability of these drugs to induce hepatic microsomal drug-metabolizing enzyme systems (as indicated by enhancement of DGA excretion) and binding behaviour at the type 1 site.

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