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At least 19 recordsLinked to original sources

PubMed1994

Studies on the active centre(s) of rat liver porphyrinogen carboxy-lyase. In vivo effect of hexachlorobenzene on decarboxylation site(s) of porphyrinogens.

1. The role of histidine on the decarboxylation of porphyrinogens of 7-, 6-, and 5-COOH III brought about by porphyrinogen carboxy-lyase (PCL) was studied. 2. For this purpose hepatic PCL from normal and hexachlorobenzene (HCB) treated rats were modified with diethylpyrocarbonate. 3. The results indicated that the enzyme from both normal and porphytic animals had histidine at the binding sites of all the porphyrinogens assayed. 4. Comparative studies between the enzyme from normal and porphyric rats suggested that in vivo HCB treatment affected the active site for the decarboxylation of 7-, 6- and 5-COOH porphyrinogens III at histidine residues. 5. On the other hand arginine modification by 2,3-butanedione treatment altered 5-COOH porphyrinogen III decarboxylation for both enzymes. However this amino acid was not involved at the binding site of this substrate.

Animals↗

PubMed1988

Attenuation of porphyrinogen oxidation by glutathione in vitro and reversal by porphyrinogenic trace metals.

We have employed a model in vitro system for iron-peroxide-catalyzed oxidation of porphyrinogens to investigate the potential role of glutathione (GSH) in trace metal-induced porphyrias. GSH strongly attenuates porphyrinogen oxidation at biologically relevant concentrations in a dose-dependent manner. Porphyrinogenic trace metals reduce the effectiveness of GSH as a porphyrinogen antioxidant, leading to significantly higher rates of porphyrinogen oxidation to porphyrins. These observations may, in part, underlie the etiology of porphyrinurias induced during prolonged trace metal exposures.

Arsenates↗

PubMed2002

Novel copper(II) induced formation of a porphyrinogen derivative: X-ray structural, spectroscopic, and electrochemical studies of porphyrinogen complexes of Cu(II) and Co(III) complex of a trispyrazolyl tripodal ligand.

Copper(II) complexes of a novel pyrazole containing porphyrinogen and cobalt(III) and zinc(II) complexes of a pyrazole containing tripodal ligand having N-donor atoms have been investigated. 5-Methyl-3-formylpyrazole (MPA) on reaction with copper(II) nitrate or perchlorate in the presence of tris(2-aminoethyl)amine (tren) forms novel pyrazole-based porphyrinogen complexes [Cu(T(3)-porphyrinogen)(H(2)O)](NO(3))(2) (1a) and [Cu(T(3)-porphyrinogen)(H(2)O)](ClO(4))(2) (1b) where T(3)-porphyrinogen is 1,6,11,16-tetraaza-5,10,15,20-tetrahydroxy-2,7,12,17-tetramethylporphyrinogen. The same products are also obtained when tren is replaced by triethylamine. By contrast, the reaction between MPA, tren, and cobalt(II) perchlorate produces the cobalt(III) complex [Co(HMPz(3)tren)]ClO(4) (2) derived from the tripodal Schiff base tris[4-(3-(5-methyl-pyrazolyl)-3-aza-3-butenyl]amine (H(3)MPz(3)tren). The X-ray crystal structures of the copper(II) complexes (1a and 1b) and the cobalt(III) complex (2) have been determined. The structures show distorted square pyramidal coordination environments for 1a and 1b with the water molecule occupying the apical site, while for complex 2 a distorted octahedral geometry is obtained. Data for 1a follow: a = 19.476(3) A, b = 9.4116(8) A, c = 14.204(3) A; alpha = 90 degrees = gamma, beta = 107.58(2) degrees; V = 2482.0(7) A(3), Z = 4. Data for 1b follow: a = 20.967(3) A, b = 9.1563(18) A, c = 14.858(4) A; alpha = 90 degrees = gamma, beta = 108.44(3) degrees; V = 2706.0(10) A(3), Z = 4. Data for 2 follow: a = 21.293(3) A, b = 12.724(2) A, c = 19.777(4) A; alpha = 90 degrees = gamma, beta = 93.03(2) degrees; V = 5350.6(15) A(3), Z = 8. All three complexes crystallize in the monoclinic crystal system with the C2/c space group. The complexes are further characterized by UV-vis, IR, EPR, and electrochemical studies.

Journal Article↗

PubMed1987

Liver porphyrinogen carboxylase in hexachlorobenzene porphyric rats. Studies with intermediate porphyrinogens of series III and with uroporphyrinogen I.

The present work studies the action of hexachlorobenzene (HCB) on the decarboxylation of uroporphyrinogen (Urogen) I and III and also on the decarboxylation of intermediate porphyrinogens of series III under different conditions using liver of normal and porphyric rats as enzyme source. The same enzyme is involved in the Urogen decarboxylation of both isomeric series I and III and catalyses the four steps in both cases. HCB affects all of them. HCB blocks the four steps of Urogen III decarboxylation to the same degree, as a function of intoxication time. HCB leads, in general, to an increase in the efficiency (Km/Vmax) of the porphyric system. These data can be interpreted as a reaction of the organism to overcome the enzymatic blockade.

Animals↗

PubMed2005

Direct incorporation of a ferric ion in the porphyrinogen core: tetrakis(cyclohexyl)iron porphyrinogen anion with different conformers and its reaction with iodine.

Et(4)N[L' 'Fe(III)].3DCM (1) is directly synthesized by adding ferric chloride into a solution of a lithium salt of tetrakis(cyclohexyl)porphyrinogen (L' '). [L' '](4-) is a good chelating ligand for both Fe(III) and Fe(II) ions. It is an avid proton scavenger but not a reducing agent. 1 showed a magnetic moment (mu(eff)) of 4.3 micro(B) in the solid, which changed to 6.0 micro(B) in solution. This change in spin state is common for all iron porphrinogens. 1 showed polymorphism, and with pyridine in the lattice, it changed to Et(4)N[L' 'Fe(III)].DCM(0.5)Py(1.5) (2), possessing two different conformers. Calculation of these conformers at the density functional theory level showed the relative energies of all d orbital changes in three conformers, highlighting the influence of the disposition of a peripheral ligand. Iodine oxidation of 1 yielded [L' '(DeltaDelta)Fe(II)I][I(3).I(2)(+).I(3)(-)] (3) with the introduction of two C(alpha)-C(alpha) bonds with concomitant reduction of Fe(III) to Fe(II). Its mu(eff) (5.4 mu(B)) in the solid changed to 4.8 micro(B) in solution, suggesting a high spin state (S = 2) for Fe(II).

Anions↗

PubMed1999

Porphyria-induced hepatic porphyrinogen carboxy-lyase inhibitor and its interaction with the active site(s) of the enzyme.

Porphyrinogen carboxy-lyase is an enzyme that sequentially decarboxylates uroporphyrinogen III (8-COOH) to yield coproporphyrinogen III (4-COOH). In mammals this enzyme activity is impaired by hexachlorobenzene treatment, through generation of an enzyme inhibitor. The interaction of porphyrinogen carboxy-lyase inhibitor, extracted from the liver of hexachlorobenzene-treated rats, with substrate decarboxylation sites on the enzyme, was studied using four different carboxylated substrates belonging to the isomeric III series of naturally-formed porphyrinogens containing 8-,7-,6- and 5-COOH. Similar inhibitor effects were elicited against all the substrates assayed, with the exception of pentacarboxyporphyrinogen III in which decarboxylation was not inhibited to same extent. Enzyme protection assays in the presence of the different substrates, indicated that each porphyrinogen protects its own decarboxylation from inhibitor action. Preincubation of the inhibitor with normal enzyme increased its inhibitory effect. On the other hand, preincubation of both enzyme and inhibitor with superoxide dismutase or mannitol, did not alter inhibitory activity. Preincubation of the inhibitor with a number of amino acids showed that only arginine and its derivative N alpha-Benzoyl-L-Arginine ethyl ester interact with the inhibitor, noticeably reducing its ability to inhibit porphyrinogen carboxy-lyase. Albumin, histidine, serine, cysteine and imidazol, were unable to quench inhibitor activity. The present results indicate that the inhibitor acts at the binding site of each porphyrinogen. Taking into account that arginine is related to enzyme activity, and that histidine is found at the binding site of the substrates, the results suggest that the inhibitor could bind to arginine residues, blocking the access of substrates to histidine and altering the adequate orientation for decarboxylation by masking the positively charged active site necessary for porphyrinogen binding to the enzyme. In addition an indirect effect of the inhibitor mediated through free radicals could be discarded.

Animals↗

PubMed1982

Porphyrinogens in urine in various types of porphyrias.

Porphyrinogens were determined in very fresh, diluted morning urine in two types of hepatic porphyria, using a simple and very quick spectrophotometric method. It was shown that acidification by itself is insufficient for the complete conversion of colourless porphyrinogens into porphyrins in photometric determination of porphyrins in diluted urine. A correlation was shown between percentual content of porphyrinogens and the sum of pentacarboxyporphyrins and coprophyrin. A difference was found between the excretion of porphyrinogens in morning fresh urine in porphyria cutanea tarda (average porphyrinogen fraction 22.5%, SD 10.3% of total porphyrins) and in acute intermittent porphyria (average porphyrinogen fraction 77.1%, SD 9.3% of total porphyrins). The method is at the same time suitable for the detection of urobilinoids in urine. Oxidation of the urine in acute intermittent porphyria is recommended before absorption on talc and subsequent thin-layer chromatography, because porphyrinogens are not adsorbed on talc.

Adult↗

PubMed1976

Tetrapyrroles as substrates and inhibitors of porphyrinogen carboxy - lyase from rat liver.

Porphyrinogen carboxy-lyase is an enzyme of the haem pathway which catalyses the stepwise decarboxylation of porphyrinogens with different number of carboxyl groups. This enzyme has a low substrate specificity since at least eighteen porphyrinogens were proved to be decarboxylated by the enzyme. In order to clarify this complex process of decarboxylation, studies were carried out using a purified enzyme preparation from rat liver. We studied the behavior of the enzyme in the presence of uroporphyrinogens I, II, III, and IV. The effect of different porphyrins, porphyrinogens and haemin on uroprophyrinogen decarboxylation was also studied to see the influence of nature and position of the side chains of pyrroles as well as the oxidation state in the tetrapyrrolic ring. The liver enzyme decarboxylates the four isomers or uroporphyrinogen. The relative accumulation of intermediates porphyrinogens formed was different from that of isomer III. Uroporphyrinogen IV is an efficient substrate for the porphyrinogen carboxyl-lyase since it was decarboxylated at higher rate than the normal uroporphyrinogen III. The elimination of a carboxyl group of an acetic acid residue located between an acetic and a propionic acid side chain appears to be easier than the one corresponding to an acetic between two propionics or between a methyl and a propionic acid residue. The presence of vicinal propionic side chains in the position 6 and 7 of the reduced porphyrin ring is an important, but not essential requirement for the binding of the enzyme to porphyrinogen. It was found that coproporphyrinogen III inhibits markedly uroporphyrinogen decarboxylation and that haemin also has inhibitory effect on this reaction. The results of the inhibitory studies suggest one or both of the propionic acid residues located in positions 2 and 4 as important factors in the tetrapyrrole enzyme binding. Some other evidence would indicate that possibly the propionic acid side chain at the position 4 may be particularly important. The reduced state of the tetrapyrrolic ring is essential for the decarboxylation process: thus would allow the side chains to adopt a steric disposition facilitating its binding to the enzyme.

Animals↗

PubMed1990

Stimulation of porphyrinogen oxidation by mercuric ion. I. Evidence of free radical formation in the presence of thiols and hydrogen peroxide.

The etiology of mercury-induced porphyrinuria was investigated by testing the hypothesis that mercuric ions (Hg2+) promote free radical-mediated oxidation of reduced porphyrins (porphyrinogens) by compromising the antioxidant potential of endogenous thiols, particularly GSH. Studies in vitro demonstrated that porphyrinogens (uroporphyrinogen and coproporphyrinogen) readily undergo H2O2-dependent oxidization in the presence of Fe3(+)-EDTA and that this action is attenuated by GSH at biologically relevant concentrations (0.5-10 mM). At low concentrations, Hg2+ complexes with GSH in a 1:2 molar ratio to decrease the antioxidant effect of GSH. However, at Hg2+ concentrations approaching saturation-complexation with available GSH, stimulation of porphyrinogen oxidation to 2 to 3 times that mediated by the H2O2/Fe3(+)-dependent system alone is observed. Stimulation of porphyrinogen oxidation by Hg2+ plus GSH increases in a dose-related manner with the concentration of H2O2 in the reaction mixture but is independent of the presence of iron. No porphyrinogen oxidation is observed in reaction mixtures containing H2O2 and either Hg2+ or GSH alone or when Hg+ is substituted for Hg2+. Studies with reactive oxidant scavengers and ESR spectroscopy suggest the participation of free radical species in Hg:GSH-mediated porphyrinogen oxidation. A mechanism involving ligand exchange between Hg2+ and GSH, which leads to formation of GS radicals and subsequent propagation of reactive oxygen-based radical species, is proposed. These studies support the view that Hg2+ both compromises the antioxidant potential of GSH and promotes formation of reactive species via thiol complexation. These findings suggest a mechanistic basis underlying the porphyrinogenic as well as tissue-damaging properties of mercuric ions.

Animals↗

PubMed1990

Stimulation of porphyrinogen oxidation by mercuric ion. II. Promotion of oxidation from the interaction of mercuric ion, glutathione, and mitochondria-generated hydrogen peroxide.

Previous studies have shown that mercuric ion (Hg2+) reacts with GSH and H2O2 in vitro to form reactive species capable of oxidizing reduced porphyrins (porphyrinogens). This effect is independent of the presence of iron in the reaction mixture. The present studies demonstrate that Hg2+ and GSH can interact in biologically relevant concentrations with H2O2 generated by the mitochondrial electron transport chain to promote oxidation of porphyrinogens via comparable mechanisms. Mitochondria from rat liver or kidney readily oxidize uroporphyrinogen when H2O2 production is stimulated by the presence of a respiratory chain substrate (NADH, succinate) and an electron transport inhibitor (e.g., NaN3). Porphyrinogen oxidation by mitochondria is significantly increased by the addition of Hg2+ and GSH, in a molar ratio of approximately 3:5, to the reaction mixture. Stimulation of porphyrinogen oxidation in the presence of Hg2+ plus GSH increases proportionately with the concentration of mitochondrial protein in the reaction cuvettes but decreases with diminished H2O2 production by the electron transport chain. Studies with reactive oxidant scavengers suggest the participation of reactive oxygen species in Hg plus GSH stimulation of mitochondrial porphyrinogen oxidation. These findings support the hypothesis that Hg2+ and GSH interact with mitochondria-generated H2O2 to promote propagation of reactive oxidants or other free radical species, which, in turn, oxidize reduced porphyrins proximal to mitochondrial membranes. These results suggest a mechanistic explanation for the porphyrinogenic action of mercury compounds, as well as for the oxidative damage to target cell constituents associated with mercury exposure.

Animals↗

PubMed2002

Comparison of rat and human cytochrome P450 (CYP) sources of N-alkylprotoporphyrin IX. Formation after interaction with porphyrinogenic xenobiotics: studies with cDNA-expressed single CYP enzymes.

1. The porphyrinogenicity of certain xenobiotics is due to mechanism-based inactivation of selected cytochrome P450 (CYP) enzymes, with concurrent formation of N-alkylprotoporphyrins (N-alkylPPs), which disrupt control of haem biosynthesis. An ambiguity arises when extrapolating results obtained with such porphyrinogenic xenobiotics in animals to humans owing to species' differences in CYP enzymes. The objective was to use cDNA-expressed individual rat CYP enzyme preparations in microsomes prepared from baculovirus-infected insect cells to determine which rat CYP enzymes were the source of N-alkylPPs after interaction with three porphyrinogenic xenobiotics and to compare the results with formation of N-alkylPPs in individual human CYP enzyme orthologues. 2. A sensitive fluorometric technique was employed to quantitate N-alkylPP formation after interaction of individual CYP enzymes with a porphyrinogenic xenobiotic. 3. N-alkylPP formation was found following the interaction of three porphyrinogenic xenobiotics with CYP1A2, 2B1, 2C6, 2C11 and 3A2, in amounts ranging from 0.45 to 0.07 nmol N-alkylPP nmol(-1) CYP. The results obtained with rat CYP1A2, 2C6, 2C11 and 3A2 were compared with those previously obtained with the human CYP orthologues 1A2, 2C9 and 3A4. 4. Some results corresponded while others did not, reinforcing a previous recommendation that when dealing with xenobiotics whose porphyrinogenicity depends upon interaction with CYP enzymes resulting in N-alkylPP formation, animal experiments should be augmented with studies using human CYP preparations.

Animals↗

PubMed2002

Identification of human hepatic cytochrome P450 sources of N-alkylprotoporphyrin IX after interaction with porphyrinogenic xenobiotics, implications for detection of xenobiotic-induced porphyria in humans.

Porphyrinogenicity of certain xenobiotics depends upon mechanism-based inactivation of specific cytochrome P450 (P450) enzymes, followed by formation of N-alkylprotoporphyrin IX (N-alkylPP). Examination of the porphyrinogenicity of xenobiotics in animals and extrapolation of the results to humans is associated with ambiguity due, in part, to differences between P450 enzymes. The goal of this study was to develop an in vitro test for the detection of N-alkylPPs, produced in human liver after administration of xenobiotics found to be porphyrinogenic in animals. This goal was achieved using fluorometry to detect N-alkylPP formation following mechanism-based inactivation by porphyrinogenic xenobiotics of single cDNA-expressed human P450 enzymes in microsomes prepared from baculovirus-infected insect cells (Supersomes) and in human liver microsomes. The following combinations of P450 enzymes were major sources of N-alkylPPs in Supersomes: CYP3A4 [3-[(arylthio)-ethyl]sydnone (TTMS)]; CYP1A2 and 2C9 [3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethyl DDC)]; and CYP2C9, 2D6, and 3A4 [allylisopropylacetamide (AIA)]. Whereas similarities were found between results with human enzymes in Supersomes and their rat orthologs in rat liver microsomes, some differences were found. The results with TTMS and AIA, but not with 4-ethyl DDC, were the same in individual human enzymes expressed in Supersomes and human liver microsomes. We conclude that some differences exist between human liver P450 enzymes and their rat P450 orthologs in liver microsomes. It would therefore be prudent when dealing with xenobiotics in which porphyrinogenicity depends upon N-alkylPP formation to supplement animal data with studies using human P450 enzymes.

Animals↗

PubMedDate not supplied

Porphyrinogenic xenobiotic-induced N-alkylprotoporphyrin IX formation: a bioassay utilizing chick embryo hepatic ferrochelatase.

INTRODUCTION: The porphyrinogenicity of some xenobiotics results from mechanism-based inactivation of selected cytochrome P450 (CYP) enzymes accompanied by conversion of prosthetic heme groups to N-alkylprotoporphyrins (N-alkylPPs), some of which inhibit ferrochelatase (FC). Problems have arisen in extrapolating xenobiotic porphyrinogenicity observed in test animals to humans, due in part to differences among CYP enzymes. Our goal was to develop a bioassay to detect N-alkylPPs formed following interaction of porphyrinogenic xenobiotics with rat liver microsomal CYP. METHODS: Seventeen-day-old chick embryo livers were homogenized, and the mitochondrial fraction was isolated. The FC activity of this fraction was determined by means of the pyridine hemochromogen method. Inhibition of FC was used to detect N-alkylPP formation following interaction of porphyrinogenic xenobiotics with rat liver microsomes. RESULTS: The 17-day-old chick embryo hepatic mitochondrial preparation served as a stable source of FC activity, which was linear with respect to time and protein concentration. FC activity was higher than previously reported in a homogenate of 17-day-old chick embryo hepatocytes in culture and in an aqueous extract of 17-day-old chick embryo mitochondria. The EC(50) of N-methylprotoporphyrin IX in the chick embryo liver mitochondrial preparation was similar to that in the homogenate of chick embryo liver cell culture. The FC bioassay could detect N-alkylPPs formed following the interaction of porphyrinogenic xenobiotics with rat liver microsomes containing 2.4-9.0 nmol of CYP. DISCUSSION: In future studies investigating N-alkylPP formation following interaction of xenobiotics with CYP enzymes, we recommend using a combination of a fluorescence technique and the chick embryo hepatic mitochondrial FC assay. This would provide information both on the formation of N-alkylPPs and distinguish between those N-alkylPPs that produced porphyrin accumulation via FC inhibition and those that do not.

Animals↗

PubMed1989

Preparation, high-performance liquid chromatographic separation and characterization of hexacarboxylic porphyrinogens.

A simple method for the preparation and reversed-phase high-performance liquid chromatographic separation of hexacarboxylic porphyrinogen isomers is described. Uroporphyrin I or III was partially decarboxylated in 0.5 M hydrochloric acid at 150 degrees C. Unreacted uroporphyrin and the hepta-, hexa- and pentacarboxylic porphyrins formed were esterified and then group-separated by thin-layer chromatography. After hydrolysis, the porphyrins were reduced to the corresponding porphyrinogens with 3% (w/w) sodium amalgam. The hexacarboxylic porphyrinogens were separated on an ODS-Hypersil column by elution with acetonitrile-methanol-1 M ammonium acetate, pH 5.16 (8:12:80, v/v/v) as mobile phase. Isomers were identified by high-performance liquid chromatography of the characteristic mixture of two pentacarboxylic porphyrins formed after partial decarboxylation of individual isomers. Except for the two type I isomers, resolution of the hexacarboxylic porphyrinogens was superior to that of the corresponding porphyrins.

Chemical Phenomena↗

PubMed2005

Multielectron redox chemistry of iron porphyrinogens.

Iron octamethylporphyrinogens were prepared and structurally characterized in three different oxidation states in the absence of axial ligands and with sodium or tetrafluoroborate as the only counterions. Under these conditions, the iron- and ligand-based redox chemistry of iron porphyrinogens can be defined. The iron center is easily oxidized by a single electron (E(1/2) = -0.57 V vs NHE in CH(3)CN) when confined within the fully reduced macrocycle. The porphyrinogen ligand also undergoes oxidation but in a single four-electron step (E(p) = +0.77 V vs NHE in CH(3)CN); one of the ligand-based electrons is intercepted for the reduction of Fe(III) to Fe(II) to result in an overall three-electron oxidation process. The oxidation equivalents in the macrocycle are stored in C(alpha)-C(alpha) bonds of spirocyclopropane rings, formed between adjacent pyrroles. EPR, magnetic and Mossbauer measurements, and DFT computations of the redox states of the iron porphyrinogens reveal that the reduced ligand gives rise to iron in intermediate spin states, whereas the fully oxidized ligand possesses a weaker sigma-donor framework, giving rise to high-spin iron. Taken together, the results reported herein establish a metal-macrocycle cooperativity that engenders a multielectron chemistry for iron porphyrinogens that is unavailable to heme cofactors.

Crystallography, X-Ray↗

PubMed2000

Use of recombinant human ferrochelatase as a sensitive bioassay for N-alkylprotoporphyrin IX formed after interaction of porphyrinogenic xenobiotics with rat liver microsomes.

Several porphyrinogenic xenobiotics elicit mechanism-based inactivation of cytochrome P450 (CYP) isozymes, leading to the formation of N-alkylprotoporphyrin IX (N-alkylPP), a potent inhibitor of ferrochelatase, the terminal enzyme in heme biosynthesis. Recognizing their role in experimental porphyria, our long term objective is the establishment of an appropriate in vitro system for the detection and quantification of N-alkylPPs, formed in human liver after the administration of potential porphyrinogenic compounds. In a previous study, we used a combination of thin-layer chromatography and UV-visible spectrophotometry to isolate and identify N-alkylPPs after incubating porphyrinogenic compounds with rat liver microsomes. However, the overall yield of N-alkylPPs was low, and it was concluded that in vitro systems, such as human lymphoblastoid microsomal preparations containing single cDNA-expressed human cytochrome P450 (CYP) isozymes, do not contain sufficient CYP for in vitro studies designed to isolate N-alkylPP. In the present study we demonstrate that purified recombinant human ferrochelatase (FC) provides an extremely sensitive bioassay system for N-alkylPPs and is capable of detecting N-alkylPP in the 10(-6) nmol range. Therefore, we propose that this bioassay system might allow the use of human lymphoblastoid microsomal preparations containing single cDNA-expressed human CYP isozymes to detect N-alkylPP produced after mechanism-based (catalysis-based) CYP inactivation. If this is found to be correct it will facilitate identification of potentially porphyrinogenic drugs prior to administration to humans.

Animals↗

PubMed1986

[Evaluation of porphyrinogenic effect of lindane in rats].

In order to study the porphyrinogenic ability of lindane in mammals, rats were treated with the pesticide suspended with the aid of Tween or dissolved in oil during about 3 months. The urinary excretion of porphyrins and its precursors: delta-aminolaevulinate (ALA) and porphobilinogen (PBG), as well as the faecal excretion of coproporphyrin (COPRO) and protoporphyrin (PROTO) was determined weekly. At the end of the treatment the hepatic activities of ALA Synthase (ALA-S), the first and rate limiting enzyme of haem pathway, and porphyrinogen carboxy-lyase (PCL), enzyme which sequentially decarboxylates uroporphyrinogen (8 COOH) to coproporphyrinogen (4 COOH), were assayed. Lindane moderately increased the urinary excretion of porphyrins and its precursors, being the former the mainly affected parameter. The faecal excretion of COPRO and PROTO was also increased. However, the hepatic activity of ALA-S was not altered. This would suggest that the regulatory haem pool was not affected. Nor was PCL activity altered in spite of being the key enzyme for the attack of other chlorinated compounds. Although hexachlorobenzene (HCB), a very well known porphyrinogenic drug, and lindane are chemically related and generate similar metabolites, the last one produces a small and qualitatively different alteration of haem biosynthesis. This may be related with the absence or scarce formation of the reactive metabolite that accounts for the porphyrinogenic ability of HCB.

5-Aminolevulinate Synthetase↗

PubMed1995

Up-regulation of CYP2A5 expression by porphyrinogenic agents in mouse liver.

Coumarin 7-hydroxylase (COH) activity is catalyzed by the Cyp2a-5 gene product (CYP2A5 enzyme) in mice. Mouse hepatic CYP2A5 expression is often increased in conditions in which other P450 forms are repressed, e.g. after the administration of heavy metals and other toxic agents known to affect cellular heme balance. In this study, the effect of various porphyrinogenic chemicals on the expression CYP2A5 and the key enzymes in heme metabolism was studied. Administration of single doses of griseofulvin (1000 mg/kg), thioacetamide (10 mg/kg) and aminotriazole (1000 mg/kg) to DBA/2 and C57BL/6 mice produced up to 10-fold increases in hepatic COH catalytic activity. Dramatic, up to 130-fold increases in response to the inducers was observed in the amount of CYP2A5 steady-state mRNA. The mRNA contents of aminolevulinate synthase, ferrochelatase and heme oxygenase were also increased to a variable extent, possibly reflecting feed-back regulatory mechanisms. In D2 mice the CYP2A5 inducing effect of aminotriazole and thioacetamide, but not that of griseofulvin, pyrazole and phenobarbital, was abolished by exogenously administered heme arginate. In the B6 strain heme arginate treatment increased CYP2A5 expression but it did not affect the induction caused by porphyrinogenic agents. These results show that porphyrinogenic agents act as efficient inducers of CYP2A5, and suggest that regulation of the transcription of the Cyp2a-5 gene could in some instances involve heme-sensitive factors.

5-Aminolevulinate Synthetase↗