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PubMed1997

Development of Arabidopsis thaliana leaves at low temperatures releases the suppression of photosynthesis and photosynthetic gene expression despite the accumulation of soluble carbohydrates.

Arabidopsis thaliana plants were grown at 23 degrees C and changes in carbohydrate metabolism, photosynthesis and photosynthetic gene expression were studied after the plants were shifted to 5 degrees C. The responses of leaves shifted to 5 degrees C after development at 23 degrees C are compared to leaves that developed at 5 degrees C. Shifting warm developed leaves to 5 degrees C lead to a severe suppression of photosynthesis that correlated with a rapid and sustained accumulation of hexose phosphates and soluble sugars. Associated with the suppression of photosynthesis and the accumulation of soluble sugars was a reduction in the amount of transcript for genes encoding photosynthetic proteins (cab and rbcS). In contrast, leaves that developed at 5 degrees C showed an increase in photosynthesis and control levels of photosynthetic gene expression. This recovery occurred even though leaves that developed at 5 degrees C maintained large pools of soluble sugars. Leaves that developed at 5 degrees C also showed a strong upregulation of the cytosolic pathway for soluble sugar synthesis but not of the chloroplastic pathway for starch synthesis. This was shown at the level of both enzyme activity and the amount of transcript. Thus, development of Arabidopsis leaves at 5 degrees C resulted in metabolic changes that enabled them to produce and accumulate large soluble sugar pools without any associated suppression of photosynthesis or photosynthetic gene expression. These changes were also associated with enhanced freezing tolerance. We suggest that this reprogramming of carbohydrate metabolism associated with development at low temperature is essential to the development of full freezing tolerance and for winter survival of over-wintering herbaceous annuals.

Adaptation, Physiological↗
PubMed2000

Targeted photodestruction of human colon cancer cells using charged 17.1A chlorin e6 immunoconjugates.

The goal of this study was to develop a strategy for the selective destruction of colorectal cancer cells. Towards this end, photoimmunoconjugates were prepared between the anti-colon cancer monoclonal antibody 17.1A and the photosensitizer (PS) chlorin(e6) (c(e6)). Polylysine linkers bearing several c(e6) molecules were covalently attached in a site-specific manner to partially reduced IgG molecules, which allowed photoimmunoconjugates to bear either cationic or anionic charges. The conjugates retained immunoreactivity as shown by enzyme-linked immunosorbent assays and by competition studies with native antibody. The overall charge on the photoimmunoconjugate was an important determinant of PS delivery. The cationic photoimmunoconjugate delivered 4 times more c(e6) to the cells than the anionic photoimmunoconjugate, and both 17.1A conjugates showed, in comparison to non-specific rabbit IgG conjugates, selectivity for antigen-positive target cells. Illumination with only 3 J cm(-2) of 666 nm light reduced the number of colony forming cells by more than 90% for the cationic 17.1A conjugate and by 73% for the anionic 17.1A conjugate after incubation with 1 microM c(e6) equivalent of the respective conjugates. By contrast, 1 microM free c(e6) gave only a 35% reduction in colonies. These data suggest photoimmunoconjugates may have applications in photoimmunotherapy where destruction of colorectal cancer cells is required.

Antibodies, Monoclonal↗
PubMed2000

Biodistribution of charged 17.1A photoimmunoconjugates in a murine model of hepatic metastasis of colorectal cancer.

Optimizing photodynamic therapy involves attempting to increase both the absolute tumour content of photosensitizer and the selectivity between tumour and surrounding normal tissue. One reason why photodynamic therapy has not been considered suitable for treatment of metastatic tumours in the liver, is the poor selectivity of conventional photosensitizers for tumour compared to normal liver. This report details an alternative approach to increasing this selectivity by the use of antibody-targeted photosensitizers (or photoimmunoconjugates) to target intrahepatic tumours caused by human colorectal cancer cells in the nude mouse, and explores the role of molecular charge on the tumour-targeting efficiency of macromolecules. The murine monoclonal antibody 17.1A (which recognizes an antigen expressed on HT 29 cells) was used to prepare site-specific photoimmunoconjugates with the photosensitizer chlorine6. The conjugates had either a predominant cationic or anionic charge and were injected i.v. into tumour-bearing mice. Biodistribution 3 or 24 h later was measured by extraction of tissue samples and quantitation of chlorine6 content by fluorescence spectroscopy. The photoimmunoconjugates were compared to the polylysine conjugates in an attempt to define the effect of molecular charge as well as antibody targeting. The anionic 17.1A conjugate delivered more than twice as much photosensitizer to the tumour at 3 h than other species (5 times more than the cationic 17. 1A conjugate) and had a tumour:normal liver ratio of 2.5. Tumour-to-liver ratios were greater than one for most compounds at 3 h but declined at 24 h. Tumour-to-skin ratios were high (> 38) for all conjugates but not for free chlorine6. Cationic species had a high uptake in the lungs compared to anionic species. The photoimmunoconjugates show an advantage over literature reports of other photosensitizers, which can result in tumour:normal liver ratios of less than 1.

Adenocarcinoma↗
PubMed2001

Chlorophyllin intervention reduces aflatoxin-DNA adducts in individuals at high risk for liver cancer.

Residents of Qidong, People's Republic of China, are at high risk for development of hepatocellular carcinoma, in part from consumption of foods contaminated with aflatoxins. Chlorophyllin, a mixture of semisynthetic, water-soluble derivatives of chlorophyll that is used as a food colorant and over-the-counter medicine, has been shown to be an effective inhibitor of aflatoxin hepatocarcinogenesis in animal models by blocking carcinogen bioavailability. In a randomized, double-blind, placebo-controlled chemoprevention trial, we tested whether chlorophyllin could alter the disposition of aflatoxin. One hundred and eighty healthy adults from Qidong were randomly assigned to ingest 100 mg of chlorophyllin or a placebo three times a day for 4 months. The primary endpoint was modulation of levels of aflatoxin-N(7)-guanine adducts in urine samples collected 3 months into the intervention measured by using sequential immunoaffinity chromatography and liquid chromatography-electrospray mass spectrometry. This aflatoxin-DNA adduct excretion product serves as a biomarker of the biologically effective dose of aflatoxin, and elevated levels are associated with increased risk of liver cancer. Adherence to the study protocol was outstanding, and no adverse events were reported. Aflatoxin-N(7)-guanine could be detected in 105 of 169 available samples. Chlorophyllin consumption at each meal led to an overall 55% reduction (P = 0.036) in median urinary levels of this aflatoxin biomarker compared with those taking placebo. Thus, prophylactic interventions with chlorophyllin or supplementation of diets with foods rich in chlorophylls may represent practical means to prevent the development of hepatocellular carcinoma or other environmentally induced cancers.

Adult↗
PubMed2005

Method development and HPLC analysis of retail foods and beverages for copper chlorophyll (E141[i]) and chlorophyllin (E141[ii]) food colouring materials.

An analytical method using high performance liquid chromatography with photodiode array and fluorescence detection has been developed and applied to the determination of the food colour additives copper chlorophylls and copper chlorophyllins (E141[i] and [ii]) in foods and beverages. The analytical procedures from previously reported methods have been refined to cover a range of food colour formulations and retail foods. The method was single-laboratory validated. Recoveries of the polar copper chlorophyllins from spiked samples (at 14.5 mg/kg in all but one case) were in the range 79-109%, except for jelly sweets (49%). Recoveries of relatively non-polar copper chlorophylls were in the range 77-107% (except for 'made' jelly at 50%). The %RSD for recoveries was generally below 12%. Quantitative estimates of the total copper chlorophyll/chlorophyllin content of a small range of food commodities are reported, based on the use of trisodium copper chlorophyllin as a surrogate standard. The majority of E141-containing foods and colour formulations analysed exhibited a multiplicity of components due to the various extraction and purification processes that are used to obtain these colour additives. This was confounded by the presence of overwhelming amounts of native chlorophylls in certain samples (e.g. mint sauce). Food commodities containing significant amounts of emulsifiers (i.e. ice cream), gelatine or fats were problematic during extraction hence further development of extraction regimes is desirable for such products. All of the samples analysed with added E141, had estimated total copper chlorophyllin contents of below 15 mg/kg (range 0.7-13.0).

Acids↗
PubMed2004

RNA adducts with chlorophyll and chlorophyllin: stability and structural features.

Porphyrins and their metal derivatives are strong nucleic acids binders. Some of these compounds have been used for radiation sensitization therapy of cancer and are targeted to interact with cellular DNA. Chlorophyll (Chl) binds DNA via guanine N-7 atom (major groove) and the backbone phosphate group (Neault and Tajmir-Riahi. Biophys. J. 76, 2177, 1999), whereas chlorophyllin (Chln) intercalates into A-T and G-C regions (Neault and Tajmir-Riahi. J. Phys. Chem. B. 102, 1610, 1998). This study was designed to examine the interaction of RNA with chlorophyll a and chlorophyllin in aqueous solution at physiological pH with pigment/RNA(phosphate) ratios (r) of 1/80 to 1/2. Fourier transform infrared (FTIR) and UV-visible difference spectroscopic methods were used to characterize the nature of pigment-RNA interaction and to establish correlation between spectral changes and the pigment binding mode, binding constant, RNA secondary structure and structural variations of pigment-RNA complexes in aqueous solution. Spectroscopic results showed that Chl and Chln bind RNA through G-C and A-U bases and the backbone phosphate group with overall binding constants of KChl = 1.95 x 10(5) M(-1) and KChln = 1.61 x 10(5) M(-1). The larger K value obtained for Chl-RNA complexes is attributed to the formation of more stable five or six-coordinate Mg cation in the RNA adducts, while the four-coordination Cu(II) in Chln can be more stable than that of the five or six-coordinated copper ion in the Chln-RNA complexes. Aggregation of pigment-RNA complexes occurs at high metalloporphyrin concentrations. No biopolymer secondary structural changes were observed upon pigment interaction and RNA remains in the A-family structure in these pigment complexes.

Antimutagenic Agents↗
PubMed2001

Scavenging of reactive oxygen species by chlorophyllin: an ESR study.

The antioxidant effects of chlorophyllin (CHL), a water-soluble analog of the green plant pigment chlorophyll, on different reactive oxygen species (ROS) were investigated by electron spin resonance (ESR) spectroscopy. As a standard, we have used the ability of CHL to scavenge the stable 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. CHL inhibits the formation of 5,5-dimethyl-1-pyrroline-N-oxide adduct with hydroxyl radical (DMPO-.OH adduct) generated by gamma-radiation in a dose-dependent manner. At a concentration of 1 mM, CHL caused more than 90% inhibition of ESR signal intensity of this adduct. However, the results obtained with the Fenton reaction were different. We also found evidence for the inhibition of 1O2-dependent formation of the 2,2,6,6-tetramethyl-piperidine oxide (TEMPO) radical during photosensitization of methylene blue with visible light. CHL was also able to inhibit hydrogen peroxide induced oxidation of phenol red. The rate constant of the reaction of CHL with H2O2 was found to be 2.7 x 10(6) M-1 s-1. In conclusion, CHL has potent antioxidant ability involving scavenging of various physiologically important ROS.

Bepridil↗
PubMed2005

Copper- and magnesium protoporphyrin complexes inhibit oxidative modification of LDL induced by hemin, transition metal ions and tyrosyl radicals.

The oxidative modification of LDL may play an important role in the early events of atherogenesis. Thus the identification of antioxidative compounds may be of therapeutic and prophylactic importance regarding cardiovascular disease. Copper-chlorophyllin (Cu-CHL), a Cu(2+)-protoporphyrin IX complex, has been reported to inhibit lipid oxidation in biological membranes and liposomes. Hemin (Fe(3+)-protoporphyrin IX) has been shown to bind to LDL thereby inducing lipid peroxidation. As Cu-CHL has a similar structure as hemin, one may assume that Cu-CHL may compete with the hemin action on LDL. Therefore, in the present study Cu-CHL and the related compound magnesium-chlorophyllin (Mg-CHL) were examined in their ability to inhibit LDL oxidation initiated by hemin and other LDL oxidizing systems. LDL oxidation by hemin in presence of H(2)O(2) was strongly inhibited by both CHLs. Both chlorophyllins were also capable of effectively inhibiting LDL oxidation initiated by transition metal ions (Cu(2+)), human umbilical vein endothelial cells (HUVEC) and tyrosyl radicals generated by myeloperoxidase (MPO) in presence of H(2)O(2) and tyrosine. Cu- and Mg-CHL showed radical scavenging ability as demonstrated by the diphenylpicrylhydracylradical (DPPH)-radical assay and estimation of phenoxyl radical generated diphenyl (dityrosine) formation. As assessed by ultracentrifugation the chlorophyllins were found to bind to LDL (and HDL) in serum. The present study shows that copper chlorophyllin (Cu-CHL) and its magnesium analog could act as potent antagonists of atherogenic LDL modification induced by various oxidative stimuli. As inhibitory effects of the CHLs were found at concentrations as low as 1 mumol/l, which can be achieved in humans, the results may be physiologically/therapeutically relevant.

Atherosclerosis↗
PubMed1999

Photooxidative bleaching of chlorophyllin.

Chlorophyllin, a water-soluble, copper-containing porphyrin, can be bleached rapidly in the light or slowly in the dark in a reaction which is oxygen dependent. Both the photo and the dark bleaching reactions are temperature dependent. Cyclic voltammetry measurements show that the copper in the bleached and nonbleached state remains in the +2 redox state and could be readily reduced. This would imply that there is no net oxidative change to the copper during the bleaching process. FT-IR absorption spectroscopy showed vibrations characteristic of a vinyl functionality disappeared upon bleaching. Aqueous solutions of chlorophyllin were not dialyzable through dialysis tubing of molecular weight cut-off, 6000-8000 molecular weight, indicative of an aggregate chlorophyllin micelle. Analysis of products by high performance liquid chromatography showed that the chlorophyllin mixture was more complex than originally anticipated and that two components were lost from the mixture upon photobleaching. One compound that is preferentially lost upon photobleaching has been identified by mass spectral analysis as Cu(II) chlorin e6.

Chlorophyllides↗
PubMed2003

Dietary aflatoxin exposure and chemoprevention of cancer: a clinical review.

Exposure to dietary aflatoxins is considered to be an important risk factor for the development of hepatocellular carcinoma in certain regions of the world. Significant advances have recently been made in understanding the clinical toxicology of aflatoxins. These include the development and validation of biomarkers of exposure and genotoxic effect. These biomarkers are currently being utilized to explore the potential that pharmaceutical interventions may have in modifying the toxicokinetics of dietary aflatoxin exposure. Preliminary results of clinical trials with the drug oltipraz suggest that it may modify the genotoxic effects of aflatoxin B1 by inhibiting bioactivation pathways and stimulating detoxification pathways. More recent results of a clinical trial with chlorophyllin suggest that this drug may have a role in preventing dietary exposure to aflatoxin B1 by reducing its oral bioavailability. The preliminary results of these chemoprevention studies may ultimately have implications for cancer prevention in high-risk populations in the future.

Aflatoxins↗
PubMed1995

Superoxide dismutase (SOD) activity with Fe-chlorin e6-Na and suppression of malignant tumor growth in rats.

Derivatives of porphyrin, specifically Fe-chlorin e6-Na (FeCNa), mimic superoxide dismutase (SOD). This SOD activity was determined by decrease in electron spin resonance (ESR) signals and increase in hydrogen peroxide (H2O2) as the intermediate of O2-. by the coloration using 4-aminoantipyrin. Chlorin e6-Na used for cancer photodynamic therapy (PDT)(1) does not show SOD mimicking activity. The specific activity of FeCNa, comparing with bovine RBC-SOD, was 1/7.5 as determined by ESR analysis. The iron element of Fe-chlorin e6-Na, being tightly encased in the molecule, did not participate in the Fenton reaction. The SOD mimetic activity of FeCNa was stable against physico-chemical treatment such as pH shock, heat and digestion by pronase. For cancer bearing rats with oxidative stress (OS), immediate relief of OS was possible by a single intraperitoneal injection of FeCNa and relief continued for 24 hours. The subsequent administration of FeCNa suppressed cancer growth in vivo.

Animals↗
PubMed1989

Inhibitory effect of chlorophyll on the genotoxicity of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2).

Genotoxicity of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) on Drosophila was suppressed by chlorophyll. Using the wing hair spot test, we found that the formation of mutant hairs in adult flies as a result of feeding them with Trp-P-2 in their larval stage was efficiently inhibited by coadministration of chlorophyll. The decrease in the spot frequencies was dependent on the dose of chlorophyll, and at the highest dose used, where the ratio in weight of Trp-P-2 to chlorophyll was 1:80, a complete prevention of the small single-spot formation was observed. A similar inhibitory effect was detected for chlorophyllin, the chromophore of chlorophyll. In the studies to investigate the mechanism of inhibition, we observed that the mutagenicity of 3-hydroxy-amino-1-methyl-5H-pyrido[4,3-b]indole [Trp-P-2(NHOH)], the metabolically activated form of Trp-P-2, in Salmonella typhimurium TA98 was suppressed effectively with chlorophyll and chlorophyllin. We also found that chlorophyll and chlorophyllin can produce complexes with Trp-P-2 and Trp-P-2(NHOH). A straightforward mechanism of these inhibitions is that Trp-P-2 [and Trp-P-2(NHOH)] becomes no longer available to organisms on forming the chlorophyll complex.

Animals↗
PubMed1991

Chemopreventive properties of chlorophyllin: inhibition of aflatoxin B1 (AFB1)-DNA binding in vivo and anti-mutagenic activity against AFB1 and two heterocyclic amines in the Salmonella mutagenicity assay.

Chlorophyllin (CHL), a sodium/copper derivative of chlorophyll, has been used to treat a number of human conditions with no toxic effects being reported. Recent studies have described the anti-mutagenic activity of CHL in several short-term genotoxicity assays; however, this compound has not been reported to inhibit carcinogen--DNA binding in vivo, and it has yet to be evaluated as an anti-carcinogen in any species. The chemopreventive properties of CHL were studied in trout using inhibition of aflatoxin B1 (AFB1)--DNA binding as an end-point. Chlorophyllin and AFB1 were coadministered in the diet, and carcinogen--DNA binding levels were determined in liver after 1, 3, 5 and 7 days. Linear increases in AFB1--DNA binding occurred with time of treatment at each CHL dose level (0, 500, 1000 and 2000 p.p.m.). Each increase in CHL dose produced a concomitant decrease in AFB1--DNA binding, resulting in a series of curves of decreasing slope. At the highest CHL dose level of 2000 p.p.m., AFB1--DNA binding was inhibited by 70%. These results suggest that CHL should be a potent inhibitor of AFB1-induced hepatocarcinogenesis in this model. In the Salmonella assay, CHL exhibited potent anti-mutagenic activity against AFB1 and two heterocyclic amines when incubated in the presence of trout liver activation systems. CHL also inhibited the mutagenic activity of AFB1-8,9-epoxide in the absence of a metabolic activation system. Dietary CHL substantially inhibited liver AFB1-DNA binding in vivo, even when AFB1 was given by i.p. injection to avoid direct AFB1--CHL interaction in the diet or gut. Collectively, these studies support a CHL inhibitory mechanism involving complex formation with the carcinogen in the gut coupled with electrophile scavenging or further complexing in the target organ.

Aflatoxin B1↗
PubMed1992

Protection by chlorophyllin against the covalent binding of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) to rat liver DNA.

Chlorophyllin (CHL), a sodium/copper salt of chlorophyll used in the treatment of geriatric patients, exhibits potent antimutagenic activity in a range of assays in vitro and in vivo. The protective effects of CHL were studied in Sprague-Dawley rats using inhibition of carcinogen-DNA binding as an end-point. Animals were administered CHL (150 mg/kg body wt) and [2-14C]2-amino-3-methylimidazo[4,5-f]quinoline (IQ, 50 mg/kg body wt) by single oral gavage. Covalent IQ-DNA binding in liver was determined 8, 24 and 48 h after dosing; CHL inhibited binding at these times by 58, 56 and 46% respectively, compared with rats given IQ alone. The total liver burden of IQ-derived radioactivity was reduced in CHL-treated rats, as was the total amount of radiolabel eliminated in the urine and bile. However, elimination via the feces was increased in rats given CHL, both in terms of total radiolabel eliminated and amount of unmetabolized IQ in dichloromethane extracts of feces. Finally, pretreatment with CHL in the drinking water, or injection of CHL into isolated loops of intestine in situ, reduced the absorption of IQ from the gut. Collectively, these findings indicate that, when administered simultaneously with the carcinogen, CHL attenuates IQ-DNA binding in rat liver by interacting with IQ in the gut and reducing carcinogen uptake, distribution and metabolism. The results suggest that further studies should be conducted with respect to the protective mechanisms and possible anti-carcinogenic properties of CHL.

Animals↗
PubMed1992

Inhibition of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-DNA binding by chlorophyllin: studies of enzyme inhibition and molecular complex formation.

Chlorophyllin (CHL), a copper/sodium salt of chlorophyll used in the treatment of geriatric patients, is an anti-mutagen that has been demonstrated to inhibit carcinogen--DNA binding in vivo. To study the mechanism of inhibition, the microsomal metabolism of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and the kinetics of IQ--DNA binding were investigated in the presence and absence of CHL. In time-course studies, CHL produced greater than 80% inhibition of IQ--DNA binding and blocked the metabolism of IQ, such that 80% of the initial dose of carcinogen was recovered unmetabolized from the incubations after 1 h. Kinetic constants were determined for the in vitro DNA binding reaction, with the reaction rate measured as 'pmol IQ bound/mg DNA/min/mg microsomal protein'. Without altering V(max), the Km of the IQ--DNA binding reaction was increased by CHL, and the replot of Km/V(max) versus CHL concentration yielded a straight line with an inhibitor constant of 58.3 microM CHL. Spectrophotometric studies provided evidence in vitro for the formation of a non-covalent complex between CHL and IQ. The CHL--IQ complex had a stoichiometric ratio of 2:1 (mole ratio method) and an apparent dissociation constant from the Benesi-Hilderbrand plot of 1.41 x 10(-4)M at pH 7.4. These results are discussed in the context of a CHL inhibitory mechanism involving enzyme inhibition and molecular complex formation.

Animals↗