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Effects of the haem precursor 5-aminolaevulinate on tryptophan metabolism and disposition in the rat.

ABSTRACT: 5-Aminolaevulinate administration to rats inhibits cerebral 5-hydroxytryptamine synthesis by decreasing tryptophan availability to the brain secondarily to activation of hepatic tryptophan pyrrolase. The results show that tryptophan metabolism and disposition can be influenced by changes in liver haem concentration, and are discussed briefly in relation to mood disorders in the hepatic porphyrias.

SUBMITTER: Badawy AA

PROVIDER: S-EPMC1148535 | biostudies-other | 1987 Nov

REPOSITORIES: biostudies-other

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Tryptophan pyrrolase in haem regulation. The mechanism of the opposite effects of tryptophan on rat liver 5-aminolaevulinate synthase activity and the haem saturation of tryptophan pyrrolase.

Project description:1. Administration of tryptophan to starved rats causes a rapid decrease in liver 5-aminolaevulinate synthase activity associated with an increase in the haem saturation of tryptophan pyrrolase. Both effects are maximally produced at 30 min by a 100 mg/kg body wt. dose of tryptophan. 2. Pb2+ prevents both effects. 3. Prevention by allopurinol or benserazide of the tryptophan-induced increase in the haem saturation of tryptophan pyrrolase renders this haem available for further repression of synthase synthesis. 4. The opposite effects on synthase activity and pyrrolase saturation with haem caused by administration of 5-aminolaevulinate, but not those by that of haematin, are potentiated by tryptophan. 5. It is suggested that tryptophan decreases 5-aminolaevulinate synthase activity and causes the initial increase in the haem saturation of tryptophan pyrrolase by enhancing the conversion of 5-aminolaevulinate into haem by a process requiring protein synthesis.

| S-EPMC1163249 | biostudies-other

Examination of mitochondrial protein targeting of haem synthetic enzymes: in vivo identification of three functional haem-responsive motifs in 5-aminolaevulinate synthase.

Project description:The initial and the terminal three enzymes of the mammalian haem biosynthetic pathway are nuclear encoded, cytoplasmically synthesized and post-translationally translocated into the mitochondrion. The first enzyme, ALAS (5-aminolaevulinate synthase), occurs as an isoenzyme encoded on different chromosomes and is synthesized either as a housekeeping protein (ALAS-1) in all non-erythroid cell types, or only in differentiating erythroid precursor cells (ALAS-2). Both ALAS proteins possess mitochondrial targeting sequences that have putative haem-binding motifs. In the present study, evidence is presented demonstrating that two haem-binding motifs in the leader sequence, as well as one present in the N-terminus of the mature ALAS-1 function in vivo in the haem-regulated translocation of ALAS-1. Coproporphyrinogen oxidase, the antepenultimate pathway enzyme, possesses a leader sequence that is approx. 120 residues long. In contrast with an earlier report suggesting that only 30 residues were required for translocation of the coproporphyrinogen oxidase, we report that the complete leader is necessary for translocation and that this process is not haem-sensitive in vivo. PPO (protoporphyrinogen oxidase) lacks a typical mitochondrial targeting leader sequence and was found to be effectively targeted by just 17 N-terminal residues. Bacillus subtilis PPO, which is very similar to human PPO at its N-terminal end, is not targeted to the mitochondrion when expressed in mammalian cells, demonstrating that the translocation is highly specific with regard to both the length and spacing of charged residues in this targeting region. Ferrochelatase, the terminal enzyme, possesses a typical N-terminal leader sequence and no evidence of a role for the C-terminus was found in mitochondrial targeting.

| S-EPMC1134803 | biostudies-literature

The role of haem in the regulation of rat liver tryptophan metabolism.

Project description:At saturating concentrations of tryptophan, the activity of tryptophan 2,3-dioxygenase was the same in isolated liver cells and in extracts with added haematin. Intraperitoneal injection of haematin did not increase tryptophan oxidation in livers subsequently perfused in situ. Preincubation of liver cells with physiological concentrations of tryptophan caused maximal saturation of tryptophan 2,3-dioxygenase with haem in liver cells. In cell-free extracts tryptophan 2,3-dioxygenase exhibited complex kinetics with haem. The results have important implications for the understanding of the role of haem in tryptophan metabolism.

| S-EPMC1147402 | biostudies-other

Tryptophan pyrrolase in haem regulation. Experiments with administered haematin and the relationship between the haem saturation of tryptophan pyrrolase and the activity of 5-aminolaevulinate synthase in rat liver.

Project description:1. Administration of haematin to rats decreases 5-aminolaevulinate synthase activity in whole liver homogenates. 2. An inverse relationship between this decrease and the increase in saturation of apo-(tryptophan pyrrolase) with haem is observed during the initial phase of treatment with haematin. 3. Significant changes in both functions are caused by a 1 mg/kg dose of haematin, whereas the maximum effects are achieved by the 5 mg/kg dose. 4. Prevention by allopurinol of the conjugation of exogenously administered haematin with apo-(tryptophan pyrrolase) renders this haem available for further repression of 5 aminolaevulinate synthase. 5. The various aspects of the relationship between synthase activity and the haem saturation of tryptophan pyrrolase are discussed.

| S-EPMC1162354 | biostudies-other

Tryptophan pyrrolase in haem regulation. The relationship between the depletion of rat liver tryptophan pyrrolase haem and the enhancement of 5-aminolaevulinate synthase activity by 2-allyl-2-isopropylacetamide.

Project description:Rat liver tryptophan pyrrolase haem is maximally depleted at 30 min after administration of a 400 mg/kg dose of 2-allyl-2-isopropylacetamide. This depletion lasts for 24 h, by which time 5-aminoleevulinate synthase activity becomes maximally enhanced. 2. though the above maximum depletion of pyrrolase haem (at 0.5h) is also produced by a 100 mg/kg dose of the porphyrogen, this does not enhance synthase activity at 24 h. It and smaller doses, however, cause a smaller but earlier enhancement of synthase activity (maximum at 2 h) and produce a similarly short-lived deplation of pyrrolase haem. 3. The depletion of pyrrolase haem and the enhancement of synthase activity by the porphyrogen are inhibited by compound SKF 525-A and phenazine methosulphate, and are potentiated by nicotinamide but not by phenobarbitone. Phenazine methosulphate and nicotinamide also exert opposite effects on hexobarbital sleeping-time. 4. 2-Allyl-2-isopropylacetamde also the depletes pyrrolase haem in vitro. It does so in liver homogenates of control rats in the presence, and in those of phenobarbitone-treated rats in the absence of added NADPH. 5. A discussion of the present results in relation to previous work with other haemoproteins suggests that, whereas cytochrome P-450 (haem) is primarily involved in the production of the active (porphyrogenic) metabolite(s) of 2-allyl-2-isopropylacetamide, the haem pool used by tryptophan pyrrolase may play an important role in the effects of this compound on haem biosynthesis.

| S-EPMC1161712 | biostudies-other

Tryptophan and tryptophan pyrrolase in haem regulation. The role of lipolysis and direct displacement of serum-protein-bound tryptophan in the opposite effects of administration of endotoxin, morphine, palmitate, salicylate and theophylline on rat liver 5-aminolaevulinate synthase activity and the haem saturation of tryptophan pyrrolase.

Project description:1. The increase in the haem saturation of rat liver tryptophan pyrrolase caused by tryptophan administration was previously shown to be associated with a decrease in 5-aminolaevulinate synthase activity. 2. It is now shown that similar reciprocal effects are caused by palmitate and salicylate, both of which increase tryptophan availability to the liver by direct displacement of the serum-protein-bound amino acid. 3. The reciprocal effects on the former two parameters caused by endotoxin and morphine are associated with an increase in liver tryptophan concentration produced by a lipolysis-dependent, non-esterified fatty acid-mediated, displacement of the serum-protein-bound amino acid. 4. All these changes and those caused by another lipolytic agent, theophylline, are prevented by the beta-adrenoceptor-blocking agent propranolol and by the opiate-receptor antagonist naloxone, whose anti-lipolytic nature is demonstrated. 5. High correlation coefficients have been obtained for one or more pairs of the following parameters: serum non-esterified fatty acid concentration, free serum tryptophan concentration, liver tryptophan concentration, liver 5-aminolaevulinate synthase activity, liver holo-(tryptophan pyrrolase) activity and the haem saturation of liver tryptophan pyrrolase. 6. It is suggested that liver tryptophan concentration may play an important role in the regulation of 5-aminolaevulinate synthase synthesis, and that the latter may be subject to control by changes in lipid metabolism and may be influenced by pharmacological agents that affect tryptophan disposition. 7. Preliminary evidence suggests that tryptophan may be bound in the liver and that such a possible binding may control its availability for its hepatic functions.

| S-EPMC1158610 | biostudies-other

Metabolism and disposition of opicapone in the rat and metabolic enzymes phenotyping.

Project description:Opicapone (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide) is a selective catechol-O-methyltransferase inhibitor that has been granted marketing authorization in Europe, Japan, and United States. The present work describes the metabolism and disposition of opicapone in the rat obtained in support to its development and regulatory filling. Plasma levels and elimination of total radioactivity were determined after oral and intravenous administration of [14 C]-opicapone. The maximum plasma concentrations of opicapone-related radioactivity were reached at early time points followed by a gradual return to baseline with a biphasic elimination. Fecal excretion was the primary route of elimination of total radioactivity. Quantitative distribution of drug-related radioactivity demonstrated that opicapone and related metabolites did not distribute to the central nervous system. Opicapone was extensively metabolized in rats resulting in more than 20 phase I and phase II metabolites. Although O-glucuronidation, -sulfation, and -methylation of the nitrocatechol moiety were the principal metabolic pathways, small amount of the N-acetyl derivative was detected, as a result of reduction of the nitro group and subsequent conjugation. Other metabolic transformations included N-oxide reduction to the pyridine derivative and reductive cleavage of 1,2,4-oxadiazole ring followed by further conjugative reactions. Reaction phenotyping studies suggested that SULT 1A1*1 and *2 and UGT1A7, UGT1A8, UGT1A9, and UGT1A10 may be involved in opicapone sulfation and glucuronidation, respectively. However, the reductive metabolic pathways mediated by gut microflora cannot be excluded. Opicapone, in the rat, was found to be rapidly absorbed, widely distributed to peripheric tissues, metabolized mainly via conjugative pathways at the nitro catechol ring, and primarily excreted via feces.

| S-EPMC8929358 | biostudies-literature

Effect of endotoxin on tryptophan pyrrolase and delta-aminolaevulinate synthase: evidence for an endogenous regulatory haem fraction in rat liver.

Project description:Endotoxin was administered to rats at a dose shown previously to stimulate hepatic haem oxygenase activity and to block induction of delta-aminolaevulinate synthase, apparently by causing redistribution of haem from cytochrome P-450 to a regulatory haem pool in the liver. Within 5h of the administration of endotoxin (at a time when the effect of the compound on cytochrome P-450 is maximal) the relative saturation of tryptophan pyrrolase with intrinsic haem rose, from a basal value of 50% to 90%, indicating that 'free' haem had become available. Concurrently, the activity of delta-aminolaevulinate synthase was decreased to 25% of its basal value. Haem oxygenase reached peak activity 13h after endotoxin administration. These findings provide new evidence for the existence of an 'unassigned' hepatic haem fraction, which exchanges with cytochrome P-450 haem and regulates these three enzyme functions.

| S-EPMC1165006 | biostudies-other

The effect of exogenous -aminolaevulinate on rat liver haem and cytochromes.

Project description:The activity of delta-aminolaevulinate synthetase is generally regarded as rate-limiting for hepatic haem biosynthesis. It has been suggested that cytochrome synthesis may also be regulated by changes in delta-aminolaevulinate synthetase activity. This hypothesis was studied by injecting product, delta-aminolaevulinate, into adult rats over a 4-240h period. The concentrations of hepatic mitochondrial cytochromes a, b, c and c(1) were unchanged by treatment with delta-aminolaevulinate, allylisopropylacetamide or phenobarbital. In control animals, total microsomal haem content equalled the sum of cytochromes b(5) plus P-450. After delta-aminolaevulinate administration the total amount of microsomal haem, measured as the pyridine haemochromogen, exceeded these components, indicating the formation of a ;free' haem pool. Haem synthesis does not appear rate-limiting for hepatic cytochrome synthesis in the adult rat.

| S-EPMC1174267 | biostudies-other

Regulation of rat liver tryptophan pyrrolase by its cofactor haem: Experiments with haematin and 5-aminolaevulinate and comparison with the substrate and hormonal mechanisms.

Project description:1. The administration of haematin or 5-aminolaevulinate to rat enhances the activity of liver tryptophan pyrrolase; both endogenous and newly formed apoenzymes become strongly haem-saturated. Haem activation does not stabilize tryptophan pyrrolase. 2. Actinomycin D, puromycin or cycloheximide prevent the activation of the enzyme by 5-aminolaevulinate but not that by haematin. The latter is inhibited by haem-destroying porphyrogens. 3. The combined injection of either haematin or 5-aminolaevulinate with cortisol does not produce an additive effect, whereas potentation is observed when tryptophan is jointly given with either the cofactor or the haem precursor. 4. Further experiments on the substrate (tryptophan) mechanism of pyrrolase regulation are reported, and a comparison between this and the cofactor and hormonal mechanisms is made. 5. It is suggested that the substrate mechanism may also involve increased haem synthesis. 6. The role of tryptophan pyrrolase in the utilization of liver haem, and as a possible model for the exacerbation by drugs of human hepatic porphyrias, is discussed.

| S-EPMC1165766 | biostudies-other

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