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F De Matteis

Publications and source records attributed to F De Matteis.

At least 73 records · Page 4Linked to original sources
PubMed1985

Studies on the inhibition of ferrochelatase by N-alkylated dicarboxylic porphyrins. Steric factors involved and evidence that the inhibition is reversible.

The structural requirements for the inhibition of ferrochelatase by N-alkylated porphyrins were investigated and experiments carried out to explore the mechanism of enzyme inhibition. Three dicarboxylic porphyrins, all substrates of the enzyme, are strongly inhibitory when N-alkylated; in contrast, uroporphyrin and coproporphyrin (which are not substrates) do not inhibit after N-alkylation. Free carboxylic acid functions are required for inhibition, as the methyl ester derivatives are not themselves inhibitory. Porphyrins bearing the alkyl group on the pyrrole nitrogen of rings C and D are less effective inhibitors, particularly when zinc is chelated in the centre of the tetrapyrrole or the N-alkyl group is relatively large in size. The substituents at the 2- and 4-positions of the porphyrin system may also affect the inhibitory activity, particularly for the isomers with ring C and D alkylated. The zinc chelates of several N-alkylprotoporphyrins are inhibitory towards haem oxygenase, another haem-binding enzyme, and also in this case increasing the size of the alkyl group decreased the inhibitory activity, particularly for isomers with ring C or D alkylated. The inhibition could be reversed by prolonged incubation with excess porphyrin substrate, but dealkylation of the N-alkylporphyrin during enzyme inhibition could not be demonstrated. It is concluded (a) that N-alkylated dicarboxylic porphyrins compete reversibly with the porphyrin substrate for the enzyme active site and (b) that the structural and steric factors discussed above affect the inhibitory activity by modifying the affinity of the N-alkylporphyrin inhibitor for the enzyme.

Alkylation↗
PubMed1984

Drug-induced accumulation of uroporphyrin in chicken hepatocyte cultures. Structural requirements for the effect and role of exogenous iron.

The ability of drugs to cause uroporphyria in hepatocytes from 17-day-old chick embryos has been investigated and the response of the cells in culture compared with that of the intact liver of the embryos in ovo. In this chick-embryo system, drugs that cause accumulation of uroporphyrin within 19-24 h can only do so in culture; in contrast, 2-allyl-2-isopropylacetamide and 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which stimulate production of protoporphyrin, are effective both in culture and in ovo. A role of exogenous iron in worsening drug-induced uroporphyria was demonstrated in cultures of hepatocytes; iron also caused preferential accumulation of uroporphyrin from added 5-aminolaevulinate in the absence of a porphyrogenic chemical. Uroporphyria was induced in cultures of hepatocytes by drugs of widely different structures, suggesting that the primary molecular target with which they interact may be relatively aspecific in its binding characteristics. These results are briefly discussed, and two alternative hypotheses for the drug-induced effect in uroporphyrinogen metabolism are considered.

Acetamides↗
PubMed1983

The effect of N-methylprotoporphyrin and succinyl-acetone on the regulation of heme biosynthesis in chicken hepatocytes in culture.

The essential features of hepatic protoporphyria, namely inhibition of ferrochelatase, accumulation of protoporphyrin and stimulation of 5-aminolevulinic acid synthase (ALA-S) were all obtained by treating chicken hepatocytes in culture with small doses of N-methylprotoporphyrin. Both N-methylprotoporphyrin and succinyl-acetone, another inhibitor of heme biosynthesis, stimulated ALA-S when given on their own and also enhanced the stimulation of ALA-S caused by phenobarbital.

5-Aminolevulinate Synthetase↗
PubMed1983

N-alkylation of the haem moiety of cytochrome P-450 caused by substituted dihydropyridines. Preferential attack of different pyrrole nitrogen atoms after induction of various cytochrome P-450 isoenzymes.

1. 3,5-Diethoxycarbonyl-4-ethyl-1,4-dihydro-2,6-dimethylpyridine (4-ethyl-DDC) gives rise to N-ethylprotoporphyrin in the liver of rats by donating its 4-ethyl group to one of the pyrrole nitrogen atoms of haem. Four structural isomers are obtained, depending on which pyrrole nitrogen is alkylated. 2. When rats are pretreated with an inducer of cytochrome P-450, the production of N-ethylprotoporphyrin caused by 4-ethyl-DDC is greater, both in the whole animal and in hepatocytes incubated with the drug in vitro. 3. Pre-incubation of hepatocytes with 2-allyl-2-isopropylacetamide decreases the yield of N-ethylprotoporphyrin due to 4-ethyl-DDC, an effect largely reversed by adding exogenous haem. 4. The isomeric composition of N-ethylprotoporphyrin produced in vivo and in vitro depends on the cytochrome P-450 isoenzyme that predominates at the time of treatment, suggesting a role for the apo-cytochrome in directing alkylation on to one of the pyrrole nitrogens.

Alkylation↗
PubMed1982

Formation of cobalt protoporphyrin by chicken hepatocytes in culture. Relationship to decrease of 5-aminolaevulinate synthase caused by cobalt.

Cobalt protoporphyrin generated from 5-amino[4-14C]laevulinate by homogenates or primary cultures of chick embryo liver exposed to CoCl2 was found to be radioactivity unextractable by acid/acetone, when extra protein was added. The activity of ferrochelatase was required for formation of cobalt protoporphyrin since inhibition of ferrochelatase with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (in the presence of cycloheximide) inhibited formation of cobalt protoporphyrin and resulted in accumulation of protoporphyrin. Cobalt protoporphyrin was detected spectrophotometrically in hepatocyte cultures exposed to the combination of 2-allyl-2-isopropylacetamide and CoCl2: (1) as the pyridine haemochrome of the protein pellet remaining after acid-acetone extraction of the cells, or (2) as the material extracted from the protein pellet with acetic acid-pyridine-chloroform. The amount of cobalt protoporphyrin increased with increasing CoCl2 concentration as cellular haem declined. The decrease in haem was about equal to the amount of cobalt protoporphyrin that accumulated. 2-Allyl-2-isopropylacetamide and polychlorinated biphenyls were both powerful inducers of 5-aminolaevulinate synthase. The former led to protoporphyrin accumulation, whereas with the latter, uroporphyrin accumulated, probably due to a concomitant decrease in activity of uroporphyrinogen decarboxylase. The decrease in activity of 5-aminolaevulinate synthase produced by administration of CoCl2 was greater after treatment with 2-allyl-2-isopropylacetamide than after treatment with allylisopropylacetamide and 3,4,3',4'-tetrachlorobiphenyl. We conclude: (a) that cobalt protoporphyrin is readily formed in cultured hepatocytes, and (b) that its formation accounts for the action of cobalt on 5-aminolaevulinate synthase.

5-Aminolevulinate Synthetase↗
PubMed1982

Studied on cerebellar haem metabolism in the rat in vivo.

Rats were injected intraventricularly with 5-amino[4-14C]laevulinate and the radioactivity recovered in the total cerebellum homogenate and in its haem and porphyrin fractions was determined in time. Two phases could be distinguished in the decline of haem radioactivity, suggesting labelling of at least two pools of widely different turnover rates. Succinyl acetone, when injected intraventricularly, caused a marked and long-lasting inhibition of cerebellar 5-aminolaevulinate dehydratase activity and a corresponding inhibition of the incorporation of [14C]5-aminolaevulinate into cerebellar haem in vivo. Inhibition of cerebellar haem biosynthesis by succinylacetone was followed by stimulation of the first enzyme of the pathway, 5-aminolaevulinate synthase, whereas intraventricular injection of haematin led to a significant depression of the activity of the enzyme. This suggested that the cerebellar 5-aminolaevulinate synthetase is regulated by haem through a negative feedback mechanism. Rats given repeated doses of succinylacetone, so as to maintain 80% inhibition of their cerebellar 5-aminolaevulinate dehydratase activity for 5 days, failed to exhibit any obvious symptoms of toxicity but became more sensitive to the neurotoxic effects of large intraventricular doses of 5-aminolaevulinate.

5-Aminolevulinate Synthetase↗
PubMed1981

Brain 5-aminolaevulinate synthase. Developmental aspects and evidence for regulatory role.

1. Brain 5-aminolaevulinate synthase showed a peak of increased activity in the first few weeks of life, which preceded and accompanied the development of brain cytochromes. 2. In the brain of the adult rat the activity of the enzyme was only 20% of that in the liver (on a per g wet wt. basis), but it was still probably sufficient to maintain the turnover of brain cytochromes. 3. The brain synthase activity could be decreased by treatment of rats with cycloheximide or with large doses of 5-aminolaevulinate, especially when this precursor was given as the methyl ester. 4. Injected haematin and CoCl2 markedly inhibited the synthase activity in the liver but failed to affect the brain enzyme; neither was taken up by the brain in vivo. 5. It is concluded that the brain can itself produce the haem required for the synthesis and turnover of its own haemoproteins and that 5-aminolaevulinate synthase may regulate the pathway in brain as in other tissues. 6. The relevance of the present findings to the pathogenesis of the neurological symptoms of acute porphyria and to the beneficial effect of exogenous haematin in porphyric patients is briefly considered.

5-Aminolevulinate Synthetase↗
PubMed1980

Inhibition of protohaem ferro-lyase by N-substituted porphyrins. Structural requirements for the inhibitory effect.

N-Methyl mesoporphyrin was a powerful inhibitor of protohaem ferro-lyase in vitro, whereas N-ethyl mesoporphyrin and N-methyl coproporphyrin were not and neither was the newly described green pigment produced by giving rats ethylene. This suggests that the size of the substituent at a pyrrole nitrogen and also the number of carboxylic acid side chains of the substituted porphyrin are important for the inhibitory effect. Evidence that N-methyl mesoporphyrin inhibited the enzyme, whereas the ethylene-derived pigment did not, was also obtained in vivo.

5-Aminolevulinate Synthetase↗
PubMed1980

Inhibition of protohaem ferro-lyase in experimental porphyria. Isolation and partial characterization of a modified porphyrin inhibitor.

1. A modified porphyrin with inhibitory activity towards protohaem ferro-lyase was purified from the livers of mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, and partially characterized. 2. The inhibitor can be labelled by 5-amino[4-14C]-laevulinate, suggesting that it originates from pre-labelled liver haem. No radioactivity from 3,5-diethoxycarbonyl-1,4-dihydro[2,6-14C]collidine can be recovered bound to the purified abnormal porphyrin when the radioactive drug is used to induce its formation. 3. Similar modified porphyrins isolated from the livers of animals treated with 2-allyl-2-isopropylacetamide, secobarbitone or 1-ethynylcyclohexanol did not exhibit inhibitory activity toward protohaem ferro-lyase. 4. The inhibition of protohaem ferro-lyase was progressive, could be slowed down by cooling and partially prevented by preincubating the enzyme with the porphyrin substrate. Once established, inhibition could not be reversed by addition of the substrate 5. These results suggest that the modified porphyrin irreversibly inhibits protohaem ferro-lyase and may be used as a sensitive and selective reagent to titrate the number of active centres of the enzyme.

Animals↗
PubMed1980

Drug-induced conversion of liver haem into modified porphyrins. Evidence for two classes of products.

A porphyrin with inhibitory activity towards protohaem ferro-lyase (EC 4.99.1.1) was isolated from the liver of mice given either griseofulvin or isogriseofulvin. This porphyrin resembles closely in chromatographic and spectral properties the inhibitory pigment isolated after treatment with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, but differs from other green pigments that do not inhibit protohaem ferro-lyase. A hypothesis is proposed to account for the differences in properties between the two groups of pigments and for the mechanism of inhibition of the enzyme.

Animals↗