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PubMed2005

Nonplanar heme deformations and excited state displacements in nickel porphyrins detected by Raman spectroscopy at soret excitation.

We have correlated the Raman intensities of out-of-plane modes of nickel porphyrins with the nonplanar deformations of specific symmetries, i.e., static normal coordinate deformations (SNCDs) expressed in terms of irreducible representations of the unperturbed D(4h) point group. The model porphyrins Ni(II) octaethyltetraphenylporphyrin (NiOETPP), Ni(II) tetra(isopropyl)porphyrin (NiT((i)Pr)P), Ni(II) tetra(tert-butyl)porphyrin (NiT((t)Bu)P), and Ni(II) meso-tetraphenylporphyrin (NiTPP) were chosen because they exhibit significant out-of-plane deformations of different symmetries. At B-band excitation, the Raman scattering of out-of-plane modes becomes activated mostly via the Franck-Condon mechanism. Some characteristic bands from out-of-plane modes in the spectra were identified as reliable predictors of the type and magnitude of out-of-plane deformation. The gamma(10)-gamma(13) bands are indicators of ruffling (B(1u)) deformations for porphyrins, as confirmed by data for NiTPP, NiT((i)Pr)P, and NiT((t)Bu)P, where the Raman intensity increases with the magnitude of the ruffling deformation. The gamma(15)-gamma(17) bands are indicators of saddling (B(2u)) deformations, as shown by data for NiOETPP, which is highly saddled. By comparing the relative intensities of these prominent Raman bands we estimated the vibronic coupling parameters using a self-consistent analysis, and showed that they reproduce the respective B-band absorption profiles. We also identified the deformations along the lowest wavenumber normal coordinates as the predominant reason for the Raman activity of out-of-plane modes. Our results suggest that some of the normal coordinates (gamma(10) and gamma(13)) may be used as tools to quantitatively probe the nonplanar deformations of metalloporphyrins with alkyl substituents at the meso-positions. Out-of-plane deformations also increase the vibronic coupling strength of some low frequency in-plane Raman modes, namely, nu(7) and nu(8). Generally, the Raman data suggest that the excited B-state is substantially more nonplanar than the ground state. The overall larger vibronic coupling of ruffled porphyrins yields substantially larger dipole strengths for the vibronic sidebands associated with the B-state transition, so that the relative absorptivity of the B(v) band can be used as a convenient tool to probe the nonplanarity of the porphyrin macrocycle.

Algorithms↗
PubMed2007

Novel porphyrin-incorporated hydrogels for photoactive intraocular lens biomaterials.

Novel surface-modified hydrogel materials have been prepared by binding charged porphyrins TMPyP (tetrakis(4-N-methylpyridyl)porphyrin) and TPPS (tetrakis(4-sulfonatophenyl)porphyrin) to copolymers of HEMA (2-hydroxyethyl methacrylate) with either MAA (methacrylic acid) or DEAEMA (2-(diethylamino)ethyl methacrylate). The charged hydrogels display strong electrostatic interactions with the appropriate cationic or anionic porphyrins to give materials which are intended to be used to generate cytotoxic singlet oxygen (1O2) on photoexcitation and can therefore be used to reduce postoperative infection of the intraocular hydrogel-based replacement lenses that are used in cataract surgery. The UV/vis spectra of TMPyP in MAA:HEMA copolymers showed a small shift in the Soret band and a change from single exponential (161 micros) triplet decay lifetime in solution to a decay that could be fitted to a biexponential fit with two approximately equal components with tau = 350 and 1300 micros. O2 bubbling reduced the decay to a dominant (90%) component with a much reduced lifetime of 3 micros and a minor, longer lived (20 micros) component. With D2O solvent the 1O2 lifetime was measured by 1270 nm fluorescence as 35 micros in MAA:HEMA, compared to 67 mus in solution, although absorbance-matched samples showed similar yield of 1O2 in the polymers and in aqueous solution. In contrast to the minor perturbation in photophysical properties caused by binding TMPyP to MAA:HEMA, TPPS binding to DEAEMA:HEMA copolymers profoundly changed the 1O2 generating ability of the TPPS. In N2-bubbled samples, the polymer-bound TPPS behaved in a similar manner to TMPyP in its copolymer host; however, O2 bubbling had only a very small effect on the triplet lifetime and no 1O2 generation could be detected. The difference in behavior may be linked to differences in binding in the two systems. With TMPyP in MAA:HEMA, confocal fluorescence microscopy showed significant penetration of the porphyrin into the core of the polymer film samples (>150 microm). However, for TPPS in DEAEMA:HEMA copolymers, although the porphyrin bound much more readily to the polymer, it remained localized in the first 20 microm, even in heavily loaded samples. It is possible that the resulting high concentration of TPPS may have cross-linked the hydrogels to such an extent that it significantly reduced the solubility and/or diffusion rate of oxygen into the doped polymers. This effect is significant since it demonstrates that even simple electrostatic binding of charged porphyrins to hydrogels can have an unexpectedly large effect on the properties of the system as a whole. In this case it makes the apparently promising TPPS/DEAEMA:HEMA system a poor candidate for clinical application as a postoperative antibacterial treatment for intraocular lenses while the apparently equivalent cationic system TMPyP/MAA:HEMA displays all the required properties.

Bacteria↗
PubMed2006

Light-harvesting energy transfer and subsequent electron transfer of cationic porphyrin complexes on clay surfaces.

A novel energy-transfer system involving nonaggregated cationic porphyrins adsorbed on an anionic-type clay surface and the electron-transfer reaction that occurs after light harvesting are described. In the clay-porphyrin complexes, photochemical energy transfer from excited singlet zinc porphyrins to free-base porphyrins proceeds. The photochemical electron-transfer reaction from an electron donor in solution (hydroquinone) to the adsorbed porphyrin in the excited singlet state was also examined. Because the electron-transfer rate from the hydroquinone to the excited singlet free-base porphyrin is larger than that to the excited singlet zinc porphyrin, we conclude that the energy transfer accelerates the overall electron-transfer reaction.

Aluminum Silicates↗
PubMed1999

Tissue distribution and kinetics of endogenous porphyrins synthesized after topical application of ALA in different vehicles.

The use of 5-aminolaevulinic acid (ALA) is gaining increasing attention for photosensitization in photodynamic therapy of superficially localized tumours. The aim of this work was to determine the kinetics of porphyrin generation in tissues after topical application of ALA delivered in different vehicles on the skin overlying the tumour and normal skin of mice. Maximal accumulation was found in tumour 3 h after ALA application in both cream and lotion preparations. Normal and overlying tumour skin tissues showed different kinetic patterns, reflecting histological changes when the latter is invaded by tumour cells. Liver, kidney, spleen and blood porphyrins also raised from basal levels, showing that ALA and/or ALA-induced porphyrins reach all tissues after topical application. During the first 24 h of ALA topical application, precursors and porphyrins are excreted by both urine and faeces. ALA lotion applied on the skin overlying the tumour induced higher accumulation of tumoural porphyrins than cream, and lotion applied on normal skin appeared to be the most efficient upon inducing total body porphyrins. This work has demonstrated the great influence of the formulation of ALA vehicle on penetration through the skin. Knowledge of the kinetics of porphyrin generation after different conditions of ALA application is needed for the optimization of diagnosis and phototherapy in human tumours.

Adenocarcinoma↗
PubMed2005

The temperature dependence of porphyrin production in Propionibacterium acnes after incubation with 5-aminolevulinic acid (ALA) and its methyl ester (m-ALA).

Topical PDT treatment of the common skin disease acne vulgaris is now in clinical use. Propionibacterium acnes (P. acnes) is known to play an important role in acne. 5-Aminolevulinic acid (ALA) supplementation leads to an enhanced porphyrin production in the bacteria. Subsequent illumination with light of the proper wavelengths can reduce the number of bacteria and this might at least partly explain the PDT effect on acne. We have assessed the effects of temperature on P. acnes washed cell suspensions incubated for 4 h with ALA or ALA methyl ester (m-ALA). The effect on porphyrin production of both the cell suspension incubation temperature as well as the initial growth temperature of the cultivated cells prior to harvesting and use in suspension experiments was investigated. The bacterial porphyrin content was estimated from fluorescence emission spectra. It was found that incubation with ALA or m-ALA at a temperature 42 degrees C resulted in an approx. 100% and 33% increase in the total amount of PDT-relevant porphyrins produced as compared to incubation at 37 degrees C. These results support increasing the skin temperature during incubation with ALA or m-ALA in the clinic. The initial growth temperature, prior to the incubation, had no apparent effect on the ALA or m-ALA induced porphyrins. Activation energy studies indicate slightly higher temperature dependence in the case of ALA produced porphyrins as compared to m-ALA produced porphyrins (77 and 65 kJ mol(-1), respectively).

Aminolevulinic Acid↗
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↗
PubMed1985

The effect on photohaemolysis of variation in the structure of the porphyrin photosensitizer.

A comparison of the photosensitizing ability of a variety of porphyrins for photohaemolysis gives the following order of activity: protoporphyrin greater than deuteroporphyrin, mesoporphyrin, haematoporphyrin dimethyl ester much greater than haematoporphyrin diacetate, haematoporphyrin greater than haematoporphyrin monoacetate, coproporphyrin III, haematoporphyrin derivative, coproporphyrin III tetramethyl ester greater than uroporphyrin I, meso-tetra-(N-methyl-4-pyridinium)porphyrin tetratoluene-p-sulphonate, meso-tetra-(p-carboxyphenyl)porphyrin, protoporphyrin dimethyl ester, meso-tetra-(p-hydroxy-sulphonylphenyl)porphyrin tetrasodium salt, uroporphyrin III, deuteroporphyrin-3,8-disulphonic acid and protohaemin. The results for the metal-free porphyrins are rationalized in terms of solubility and partition properties, and a model is proposed for the incorporation of amphipathic porphyrins into the membrane lipid bilayer. Experiments with erythrocytes from patients with erythropoeitic protoporphyria and with normal erythrocytes to which porphyrin was added in a deuterium oxide medium do not lead to an increase in the rate of photohaemolysis. A possible explanation for this somewhat surprising observation is outlined.

Deuterium↗
PubMed1981

Biosynthesis of porphyrins and heme from gamma, delta-dioxovalerate by intact hepatocytes.

The purpose of this study was to assess the ability of hepatocytes to synthesize porphyrins and heme from delta-aminolevulinic acid derived from gamma, delta-dioxovalerate and alanine. An alternate pathway for delta-aminolevulinic acid synthesis, in contrast to the condensation of succinate and glycine by delta-aminolevulinate synthase [succinyl-CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37] has been suggested. This has been supported by the isolation of gamma, delta-dioxovalerate transaminase from liver mitochondria (Varticovski, L., Kushner, J. P. & Burnham, B. F. (1980) J. Biol. Chem. 255, 3742-3747). Gamma, delta-dioxovalerate transaminase catalyzes the formation of delta-aminolevulinic acid by a transamination reaction involving gamma, delta-dioxovalerate and alanine. To assess the significance of this alternate route, we prepared suspensions of respiring rat hepatocytes, which were incubated with optimal concentrations of various additives and then analyzed spectrophotometrically for synthesized porphyrins. No porphyrin synthesis was detected in cell suspensions incubated with succinate(1 mM) and glycine (20 mM). Cell suspensions incubated with gamma, delta-dioxovalerate (0.5-1.0 mM) and alanine (20 mM) synthesized 0.19 nmol of porphyrin per 10(7) cells per 2 hr (SD, 0.057). Cell suspensions incubated with delta-aminolevulinic acid (0.1 mM) synthesized 1.26 nmol of porphyrin per 10(7) cells per 2 hr (range, 1.18-1.32). Incubations with chemically synthesized gamma, delta-dioxo[5-14C]valerate were followed by extraction and purification of porphyrin esters and heme. Liquid scintillation counting revealed radiolabel incorporation into both porphyrins and heme. These studies demonstrate significant tetrapyrrole synthesis by the gamma, delta-dioxovalerate transaminase reaction. That gamma, delta-dioxovalerate is an important precursor of heme in vivo must be considered.

Alanine↗
PubMed1978

Urinary excretion of porphyrins in two cases of porphyria cutanea tarda during a period of various treatments.

The urinary excretion of porphyrins in two cases of porphyria cutanea tarda (PCT) has been followed during a period in which various treatments have been tried. In one patient pyridoxal-5-phosphate (P-5-P) injections lead to a dramatic increase in porphyrin excretion. In another P-5-P treatment was followed by a significant decrease in porphyrin excretion. p-Aminobenzoic acid (PABA) apparently had no effect on porphyrin excretion, while repeated phlebotomies had the expected effect. In both patients all variations in the total amount of porphyrins excreted were almost exclusively due to the variations in the amounts of heptacarboxylic porphyrin type III and uroporphyrin I. A secondary finding was an increase in hexa- and penta-carboxylic porphyrins type III without a concomitant increase in coproporphyrin III.

4-Aminobenzoic Acid↗
PubMed1993

The production of porphyrins from delta-aminolaevulinic acid by Haemophilus parainfluenzae.

Porphyrin production by the haemin-independent Haemophilus parainfluenzae in the diagnostic porphyrin test, which determines the X-factor requirement in Haemophilus spp., was analysed quantitatively by applying modern high-performance liquid chromatographic (HPLC) methods. Ion-pair reversed-phase HPLC enabled the simultaneous separation of all porphyrin intermediates and their isomers of haem biosynthesis produced by the bacteria. The pH-dependence of porphyrin production and the respective composition of the porphyrins within the bacterial cells and in the supernate were investigated. A pH optimum of 6.9-8.0 for the production of porphyrins was found and there were marked differences in the porphyrin profiles at different pH values.

Aminolevulinic Acid↗
PubMed2000

The influence of the vehicle on the synthesis of porphyrins after topical application of 5-aminolaevulinic acid. Implications in cutaneous photodynamic sensitization.

BACKGROUND: The optimal vehicle to ensure adequate penetration of 5-aminolaevulinic acid (ALA) for its use in photodynamic therapy (PDT) of skin lesions has not been determined. OBJECTIVES: We aimed to study the effects of ALA in various vehicle formulations [saline lotion with and without dimethylsulphoxide (DMSO), cream, liposomes and vaseline] after topical application in a murine subcutaneous adenocarcinoma model. METHODS: The effect of DMSO on porphyrin synthesis and ALA penetration through the skin was studied by measuring the uptake of 14C label from ALA, ALA and porphobilinogen accumulation, and some haem enzyme activities. The tissue distribution and kinetics of porphyrin synthesis after topical application of ALA entrapped in large multilamellar liposomes was also determined. RESULTS: ALA in saline lotion, alone or with 10% DMSO, proved to be the most efficient vehicle for tumour porphyrin accumulation (mean +/- SD 1.75 +/- 0.25 and 2.09 +/- 0.39 microg g-1, respectively), whereas cream and liposomes induced lower levels and identical porphyrin accumulation (0.60 microg g-1). Using ALA + DMSO saline lotion, a higher porphyrin accumulation was found in skin overlying the tumour tissue and in the first 2 mm of tumour, probably due to increased ALA penetration, or greater interconversion to porphyrins, or greater retention of ALA and/or porphyrins. CONCLUSIONS: These findings reinforce the importance of the vehicle in topical ALA-based PDT, and explain the mechanism of action of DMSO in enhancing protoporphyrin IX biosynthesis in superficial lesions.

Adenocarcinoma↗
PubMed2007

Phototoxic reaction and porphyrin fluorescence in skin after topical application of methyl aminolaevulinate.

BACKGROUND: Photodynamic therapy using topical methyl aminolaevulinate (MAL) is a new treatment modality for skin disorders. MAL is metabolized into endogenous porphyrins, which act as photosensitizers when illuminated. OBJECTIVES: To evaluate the severity and duration of skin photosensitivity after MAL application, and to investigate its relation to the presence of endogenous porphyrins. METHODS: Placebo and 160 mg g(-1) MAL creams were randomly assigned to contralateral sites located at the forearms and fingertips of 16 healthy volunteers and were applied for 3 h. The porphyrin content in the skin was monitored by in situ fluorescence measurements following cream removal. Phototoxic reaction was evaluated after exposure to a high dose of red light. RESULTS: The porphyrin fluorescence in forearm skin peaked about 1 h after the cream removal, was halved after 8 h, and was reduced by > 90% within 24 h. Most forearm sites were photosensitive at 1 and 8 h following cream removal. Six subjects were still sensitive at 24 h, and at this time point the phototoxicity was coincidental with residual porphyrin fluorescence. In general, all reactions were mild or moderate, and included pain, erythema, oedema and transient hyperpigmentation. No photosensitivity or porphyrin fluorescence was detected at 48 h. At the fingertips photosensitivity was absent except for sporadic cases of mild pain. CONCLUSIONS: Topical MAL application and exposure to red light induced mild and moderate phototoxicity. The photosensitivity ceased within 24-48 h after cream removal, and its duration was associated with the degradation of porphyrins.

Administration, Topical↗
PubMed2003

Eradication of Propionibacterium acnes by its endogenic porphyrins after illumination with high intensity blue light.

Propionibacterium acnes is a Gram-positive, microaerophilic bacterium that causes skin wounds. It is known to naturally produce high amounts of intracellular porphyrins. The results of the present study confirm that the investigated strain of P. acnes is capable of producing endogenic porphyrins with no need for any trigger molecules. Extracts from growing cultures have demonstrated emission peaks around 612 nm when excited at 405 nm, which are characteristic for porphyrins. Endogenic porphyrins were determined and quantified after their extraction from the bacterial cells by fluorescence intensity and by elution retention time on high-performance liquid chromatography (HPLC). The porphyrins produced by P. acnes are mostly coproporphyrin, as shown by the HPLC elution patterns. Addition of delta-aminolevulinic acid (ALA) enhanced intracellular porphyrin synthesis and higher amounts of coproporphyrin have been found. Eradication of P. acnes by its endogenic porphyrins was examined after illumination with intense blue light at 407-420 nm. The viability of 24 h cultures grown anaerobically in liquid medium was reduced by less than two orders of magnitude when illuminated once with a light dose of 75 J cm(-2). Better photodynamic effects were obtained when cultures were illuminated twice or three times consecutively with a light dose of 75 J cm(-2) and an interval of 24 h between illuminations. The viability of the culture under these conditions decreased by four orders of magnitude after two illuminations and by five orders of magnitude after three illuminations. When ALA-triggered cultures were illuminated with intense blue light at a light dose of 75 J cm(-2) the viability of the treated cultures decreased by seven orders of magnitude. This decrease in viability can occur even after a single exposure of illumination for the indicated light intensity. X-ray microanalysis and transmission electron microscopy revealed structural damages to membranes in the illuminated P. acnes. Illumination of the endogenous coproporphyrin with blue light (407-420 nm) apparently plays a major role in P. acnes photoinactivation. A treatment protocol with a series of several illuminations or illumination after application of ALA may be suitable for curing acne. Treatment by both pathways may overcome the resistance of P. acnes to antibiotic treatment.

Acne Vulgaris↗
PubMed1987

Patterns of porphyrin accumulation in response to xenobiotics. Parallels between results in chick embryo and rodents.

Our objective was to determine whether patterns of porphyrin accumulation produced by chemicals in chick embryo hepatocyte culture would indicate which enzyme of heme biosynthesis was inhibited. The ferrochelatase-inhibitory potency and porphyrin patterns produced by DDC, TTMS, and their analogues were studied. The protoporphyrin:coproporphyrin ratio observed was found to correlate with ferrochelatase-inhibitory activity. The results obtained in chick embryo with TTMS and DDC parallel those found in rodents. Griseofulvin has been shown to lower ferrochelatase activity and to cause the accumulation of protoporphyrin in rodent liver. In chick embryo liver cell culture, however, coproporphyrin, uroporphyrin, and heptacarboxylic acid porphyrin accumulate and ferrochelatase activity is not lowered. Uroporphyrin, heptacarboxylic acid porphyrin, and coproporphyrin are the major porphyrins to accumulate in response to PAHs (for example, 3,3',4,4'-TCBP in chick embryo liver cell culture). This may be explained by inhibition of UROD, which has been observed in chick embryo and rodent liver. Some chemicals, such as phenobarbital and nifedipine, cause the accumulation of these porphyrins in chick embryo liver cell culture, and this is explained by inhibition of UROD. These chemicals have not been reported to interfere with heme biosynthesis in the intact chick embryo or rodents; possibly protective mechanisms that are not available in the cell culture system are operative in the intact animal. It was concluded that porphyrin patterns may serve as a guide to which enzyme of heme biosynthesis is inhibited in chick embryo liver cell culture. The results obtained in the culture system with certain chemicals, such as DDC and TTMS analogues and PAHs, correspond with results in rodents. In other cases, such as with griseofulvin, the results do not correspond.

5-Aminolevulinate Synthetase↗
PubMed2002

Inactivation of human immunodeficiency virus type 1 by porphyrins.

We have evaluated the anti-human immunodeficiency virus (HIV) activity of a series of natural and synthetic porphyrins to identify compounds that could potentially be used as microbicides to provide a defense against infection by sexually transmitted virus. For assays we used an epithelial HeLa-CD4 cell line with an integrated long terminal repeat-beta-galactosidase gene. For structure-activity analysis, we divided the porphyrins tested into three classes: (i) natural porphyrins, (ii) metallo-tetraphenylporphyrin tetrasulfonate (metallo-TPPS4) derivatives, and (iii) sulfonated tetra-arylporphyrin derivatives. None of the natural porphyrins studied reduced infection by more than 80% at a concentration of 5 micro g/ml in these assays. Some metal chelates of TPPS4 were more active, and a number of sulfonated tetra-aryl derivatives showed significantly higher activity. Some of the most active compounds were the sulfonated tetranaphthyl porphyrin (TNapPS), sulfonated tetra-anthracenyl porphyrin (TAnthPS), and sulfonated 2,6-difluoro-meso-tetraphenylporphine [TPP(2,6-F2)S] and its copper chelate [TPP(2,6-F2)S,Cu], which reduced infection by 99, 96, 94, and 96%, respectively. Our observations indicate that at least some of these compounds are virucidal, i.e., that they render the virus noninfectious. The active compounds were found to inhibit binding of the HIV type 1 gp120 to CD4 and also to completely inhibit the ability of Env proteins expressed from recombinant vectors to induce cell fusion with receptor-bearing target cells. These results support the conclusion that modified porphyrins exhibit substantial activity against HIV and that their target is the HIV Env protein.

Cell Line↗
PubMed1983

Patterns of porphyrin accumulation in response to chemicals in chick embryo liver cells.

Four patterns of porphyrin accumulation were observed by high-pressure liquid chromatography when chemicals were added to chick embryo liver cells. These patterns provide a guide to the site of action of the chemicals. Protoporphyrin accumulated in response to 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC), a result consistent with its ability to inhibit ferrochelatase. Uroporphyrin and heptacarboxylic acid porphyrin accumulated in response to 3,3',4,4'-tetrachlorobiphenyl, 2,2',4,4',6,6'-hexachlorobiphenyl, and 3,5-diethoxycarbonyl-2,4,6-trimethylpyridine, a result suggesting inhibition of uroporphyrinogen decarboxylase. Coproporphyrin was the major porphyrin to accumulate in response to allylisopropylacetamide, aromatic amides, and steroids, a result suggesting inhibition of coproporphyrinogen oxidase. A mixture of uroporphyrin, heptacarboxylic acid porphyrin and coproporphyrin accumulated in response to aromatic di- and mono-esters, aliphatic diesters, and aliphatic amides. The pattern observed after addition of excess delta-aminolevulinic acid (ALA) the endogenous substrate of the pathway to the cells was proto- greater than copro- greater than uro-porphyrin. This pattern resembled that produced by DDC but by none of the other chemicals. It was concluded that porphyrin accumulation can not be attributed solely to the induction of ALA-synthetase. It appears that porphyrin-inducing chemicals exert an additional effect on one or other of the enzymes of the heme biosynthetic pathway.

Aminolevulinic Acid↗
PubMed2005

GoldIII porphyrin 1a induced apoptosis by mitochondrial death pathways related to reactive oxygen species.

Apoptosis is a tightly controlled multistep mechanism of cell death, and mitochondria are considered to play a central role in this process. Mitochondria initiate two distinct apoptosis pathways, one caspase-dependent and the other caspase-independent. In addition, mitochondrial production of reactive oxygen species (ROS) seems to play a role in cell death. Most chemotherapeutic agents induce apoptosis through at least one of these pathways. The post-initiation mechanisms of gold(III) porphyrin 1a were investigated in this study. HONE1 cells exposed to gold(III) porphyrin 1a underwent apoptosis after 24 hours. Functional proteomic studies revealed the alteration of several cytoplasmic protein expressions in HONE1 cells after treatment with the drug. These proteins include enzymes participating in energy production and proteins involved in cellular redox balance. There was a quick attenuation of mitochondrial membrane potential (DeltaPsi(m)) with the alterations of Bcl-2 family proteins, the release of cytochrome c, and apoptosis-inducing factor (AIF) following gold(III) porphyrin 1a treatment. Cytochrome c in turn activated caspase-9 and caspase-3. Cotreatment with caspase inhibitor (zVAD-fmk) showed that the activated caspases worked in conjunction with AIF-initiated apoptosis pathways. Further study showed that ROS played a part in gold(III) porphyrin 1a-induced apoptosis by regulating DeltaPsi(m). In summary, gold(III) porphyrin 1a induced apoptosis through both caspase-dependent and caspase-independent mitochondrial pathways, and intracellular oxidation affected gold(III) porphyrin 1a-induced apoptosis. These results support a role for gold(III) porphyrin 1a as a promising anticancer drug lead and as a possible novel therapeutic agent directed toward the mitochondria.

Apoptosis↗
PubMed2001

Synthesis and nucleic acid-binding properties of water-soluble porphyrins appending platinum(II) complexes.

We synthesized two water-soluble porphyrins appending platinum(II) complexes [alpha,beta-(4a) and alpha,alpha-(4b) 5,15-bis(2-trans-[PtCl(NH3)2]N-2-aminoethylaminocarbonylphenyl) 2,3,7,8,12,13,17,18-octamethylporphyrin] and studied their reactions with a variety of nucleic acids [disodium adenosine-5'-monophosphate (AMP), disodium guanosine-5'-monophosphate (GMP), disodium thymidine-5'-monophosphate (TMP), disodium cytidine-5'-monophosphate (CMP), synthetic polymer poly(dG)-poly(dC), poly(dA)-poly(dT)] by 1H-NMR, UV-vis and FAB-MS spectroscopies. Based on the denaturation experiments of synthetic nucleic acid polymers, we conclude that the presence of the porphyrins (5.6 microM) does not cause significant changes in the melting temperature of poly(dA)-poly(dT) (28 microM) (deltaT=1 degrees C) and shows reannealing. On the other hand, gradual melting of poly(dG)-poly(dC) (28 microM) occurs at a low temperature (deltaT= -27 degrees C) in the presence of the porphyrins (5.6 microM), and the solutions do not show reannealing phenomena. The results of UV-vis and 1H-NMR experiments revealed that the porphyrins bind to guanine bases and that the porphyrins bind to GMP more strongly than to the other nucleotides. The binding modes between the porphyrins and synthetic nucleic acids are affected more by the coordination of the nucleobase [poly(dG)-poly(dC)] to the Pt(II) in the porphyrins than by Coulomb and hydrophobic interactions.

Indicators and Reagents↗