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PubMed2002

Effects of storage conditions on furocoumarin levels in intact, chopped, or homogenized parsnips.

Furocoumarins represent a family of natural food constituents with phototoxic and photomutagenic properties. They are found mainly in plants belonging to the Rutaceae and Umbilliferae such as celery, carrots, and parsnips. Parsnips (Pastinaca sativa L.) have become more and more popular as a vegetable, e.g., as a constituent of or ingredient in baby food. Previous work has shown that microbial infection of parsnip roots can result in a dramatic increase in furocoumarin levels. In this study, freshly harvested parsnips were stored as whole roots, pieces (cubes), or homogenate at +4 degrees C or -18 degrees C over various time periods under standard conditions. It was found that furocoumarin concentrations (sum of five furocoumarins: angelicin, isopimpinellin, 5-methoxypsoralen, 8-methoxypsoralen, and psoralen) in freshly harvested parsnips, analyzed by HPLC after extraction with diethyl ether and sequential solid phase (reversed-phase and silica) extraction, was generally lower than 2.5 mg/kg, and storage of parsnips in any form investigated at -18 degrees C over up to 50 days did not lead to a marked increase in furocoumarin levels. In contrast, storage of whole parsnips, but not of cubes or homogenate, at +4 degrees C resulted in a marked biphasic increase of furocoumarin concentrations after 7 and 38 days of storage up to levels of about 40 mg/kg. A dramatic increase in furocoumarin concentrations up to 566 mg/kg was observed when whole parsnips obtained from the market were kept at room temperature over 53 days, resulting in a visible microbial (mold) infection. Baby food products from the German market containing parsnips as an ingredient or constituent showed furocoumarin levels < or =0.41 mg/kg, suggesting that properly stored roots/preparations have been used. It is recommended that, after harvesting, parsnips be kept at -18 degrees C or under other conditions that prevent microbial infections.

5-Methoxypsoralen↗
PubMed1994

In vitro photoinduced cytotoxicity and DNA binding properties of psoralen and coumarin conjugates of netropsin analogues: DNA sequence-directed alkylation and cross-link formation.

he synthesis, DNA binding and in vitro photoinduced cytotoxic properties of a number of minor groove and sequence-directed psoralen and coumarin conjugates of pyrrole- and imidazole-containing distamycin analogues 2-5 are described. Results from an ethidium displacement assay on calf thymus and T4 DNA suggest that like distamycin these agents bind strongly to the minor groove of DNA. The data show that these conjugates exhibit a lower AT preference than distamycin and the decrease is significantly greater for the imidazole-containing compounds. All of the compounds along with 8-methoxypsoralen, 1, were relatively noncytotoxic in the dark with only the imidazole-psoralen compound 3 giving an IC50 value below 100 microM. Following UV activation, all compounds showed an increased potency with photoinduced dose modifications in the human chronic myeloid leukemia K562 cells of > 333, 12, > 1.3, and > 2.5 for compounds 2-5, respectively, under the UV irradiation conditions employed. The psoralen-pyrrole analogue 2 was over 300 times more active following UV activation than agent 1, 250 times more potent than the corresponding coumarin conjugate 4, and 15-fold more potent than its imidazole analogue 3. Data from CD dilution (with DMF) studies show that upon irradiation with light at 366 nm, compounds 2-5 bind irreversibly to DNA. Furthermore, upon irradiation compound 2 produced interstrand cross-linked DNA in quantitative yield, with isolated DNA, at > 300- and > 3000-fold lower drug concentrations than the imidazole analogue 3 and 8-methoxypsoralen, respectively. As expected coumarin conjugates 4 and 5 did not produce any cross-linked DNA under any conditions. Since the psoralen conjugates are more phototoxic than their coumarin analogues, these results suggest that DNA interstrand cross-link formation may be an important mechanism by which they exert their biological activity in cells. In addition, the enhanced photocytotoxic potency of conjugate 2 over 3 may be related to its larger binding constant, more efficient DNA cross-linking ability, and possibly to its preference for AT-rich sequences.

Alkylation↗
PubMed1984

Phosphorus-nitrogen compounds. 24. Phosphoramide mustard carrier derivatives.

Diethylstilbestrol, psoralen, and propranolol were used as potential carrier molecules for selective concentrations of a nitrogen mustard moiety in breast, skin, and lung tissues, respectively. The propranolol derivative gave two racemic mixtures, which were tested to ascertain any differences in anticancer activity. The insertion of a P = O group between the carrier and oncolytic portions offsets the excess lipophilic contribution of the latter and possibly provides for latentiation of alkylating activity. Murine tumor testing of the phosphoramide mustard derivatives and two intermediates indicated that two compounds possessed marginal activity against mammary carcinoma and lymphocytic leukemia.

Animals↗
PubMed2005

Synthesis of 2,3-dihydro-3-hydroxy-2-hydroxylalkylbenzofurans from epoxy aldehydes. One-step syntheses of brosimacutin G, vaginidiol, vaginol, smyrindiol, xanthoarnol, and Avicenol A. Biomimetic syntheses of angelicin and psoralen.

We have developed two practical one-step syntheses of 2,3-dihydro-3-hydroxy-2-hydroxyalkylbenzofurans from readily available optically pure alpha,beta-epoxy aldehydes. Electron-deficient resorcinols react with epoxy aldehydes using either Cs2CO3 in DMF or KOH/CaCl2 in MeOH to give adducts 13, 16, 18, 20, 21, and brosimacutin G (6t). Grignard reagents prepared by low-temperature halogen-metal exchange of acetoxy iodocoumarins 35d and 40 and acetoxy bromonaphthalene 41 add to epoxy aldehyde (S)-26 to complete the first syntheses of vaginidiol (7c), vaginol (7t), smyrindiol (8c), xanthoarnol (8t), and avicenol A (9t). Acid-catalyzed fragmentation of vaginidiol or vaginol provides angelicin, while that of smyrindiol or xanthoarnol affords psoralen. In both cases, the trans isomers fragment only twice as fast as the cis isomers, possibly through the intermediacy of a common benzylic cation. This may have implications for the biosynthesis of angelicin and psoralen.

Aldehydes↗
PubMed1996

Lipophilicity determination of psoralens used in therapy through solubility and partitioning: comparison of theoretical and experimental approaches.

The aim of this study was to determine and to compare experimental and theoretical solubilities (S) as well as partition coefficients (PC) in an octanol/water system of psoralen (P), 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) and 4,5',8-trimethylpsoralen (TMP). For each psoralen, experimental results were performed in triplicate with a spectrofluorimetric technique. The measurements were achieved 10 times for each solution. The obtained order of the solubilities in pure octanol was 5-MOP approximately TMP > P > 8-MOP, while in water-saturated octanol it was expressed as follows: TMP approximately 5-MOP > P > 8-MOP. However, the following order was found for hydrophobicity: TMP > 5-MOP > 8-MOP > P. The solubility ratios (SR) in pure octanol and water were assessed (mean +/- SD): 3.13 +/- 0.01 (P), 2.60 +/- 0.01 (8-MOP), 3.75 +/- 0.01 (5-MOP), and 5.11 +/- 0.01 (TMP). In saturated phases, they were 3.27 +/- 0.01, 2.63 +/- 0.01, 3.85 +/- 0.01, and 5.32 +/- 0.01, respectively. The PCs were determined with low concentrations according to the Dearden and Bresnen32 method and they were 1.67 +/- 0.01, 1.93 +/- 0.01, 2.00 +/- 0.01, and 3.14 +/- 0.01, respectively. Solubility parameters (delta), in Hildebrand unit (H) or in (cal/cm3)1/2, were evaluated. They confirmed the polarity of psoralens, previously expressed through the PC, although the positional isomers (5-MOP and 8-MOP) revealed no difference. Hildebrand's approach to the solubility of regular solutions and Yalkowsky's concept of the solubility of nonelectrolytes and weak electrolytes in an octanol/water system permitted a comparison of the theoretical and experimental results. The perspective of this work is to use the physicochemical properties of the psoralens in practice for insuring convenient experimental assays and the prediction, in vitro, of the percutaneous absorption of these compounds.

5-Methoxypsoralen↗
PubMed1997

Should subjects who used psoralen suntan activators be screened for melanoma? Epidemiology and Prevention Subgroup, EORTC Melanoma Cooperative Group EORTC Prevention Research Division.

BACKGROUND: Psoralens are potent tanning activators that have been introduced in France and in Belgium in some tanning lotions and sunscreens. It was shown that poor tanners who ever used psoralen tanning activators display a four-fold increase in melanoma risk when compared to poor tanners using regular sunscreens. Although psoralens have now banned from suntan lotions, it is likely that the increase in melanoma risk linked to their previous use will persist for several years. METHODS: The melanoma risk attributable to psoralens use was calculated to evaluate the population at risk in France and Belgium. RESULTS: Melanoma incidence for the year 1995 was estimated to be of 10.2 per 100,000 in France and of 10.0 per 100,000 in Belgium, representing 5,900 and 1,000 melanoma cases. From the melanoma incidence among poor tanner who ever used psoralens (52 per 100,000) and estimation of the percentage of psoralen users among poor tanners, it can be derived that, for the year 1995, 267 melanoma cases could be attributed to psoralen tanning activators. CONCLUSIONS: Subjects who used psoralen suntan activators should be informed of their increased melanoma risk and be encouraged to participate in clinical programmes for early detection of melanoma, more especially when they are poor tanners and display a high naevi count. Such an action could save a significant number of lives.

Ficusin↗
PubMed2001

Inhibition of P-glycoprotein transport function by grapefruit juice psoralen.

PURPOSE: The grapefruit juice component bergamottin is known to inactivate cytochrome P450 3A4, with grapefruit juice consumption causing increased absorption and enhanced oral bioavailability of many cytochrome P450 3A4 substrates. Many of these substrates are also recognized by the efflux transporter P-glycoprotein. The gene product of MDR1 (multidrug resistance transporter), P-glycoprotein also confers protection against xenobiotics. METHODS: Using a whole ceil assay in which the retention of a marker substrate is evaluated and quantified, we studied the ability of grapefruit juice components to inhibit the function of this transporter. RESULTS: In a cell line presenting an overexpressed amount of the human transporter, the enzyme exhibited a 40 microM IC50 for inhibition by bergamottin. Additionally, using the ATP-hydrolysis assay, we showed that bergamottin increases P-gp-mediated ATP hydrolysis by approximately 2.3 fold with a Km of 8 microM. The concentration for this interaction is similar to that for CYP3A4 inactivation. CONCLUSIONS: These results suggest that observed grapefruit juice drug pharmacokinetic clinical interactions may be due to P-gp inhibition rather than or in addition to CYP3A4 inhibition. Inhibition of P-gp by citrus psoralens could present ways both to enhance bioavailability of therapies without increasing the dose and to diminish drug resistance in refractory cells.

3T3 Cells↗
PubMed2004

Genetic variation in primary metabolites of Pastinaca sativa; can herbivores act as selective agents?

Although insect herbivory has been shown to act as a selective agent on plant secondary metabolism, whether primary metabolites contribute to resistance and can respond to selection by herbivores remains untested. In the wild parsnip (Pastinaca sativa), its principal herbivore, Depressaria pastinacella, acts as a selective agent on furanocoumarin resistance factors. In this study, we determined whether webworms can, by causing differential reductions in fitness, act as selective agents on parsnip primary metabolites. Estimates of narrow-sense heritabilities were significantly different from zero for C18 fatty acids in buds and developing fruits, fructose and sorbitol in buds, fructose, myo-inositol, bergapten, and psoralen in fruits. Wild parsnips protected from webworms by insecticide produced 2.5 times as much seed biomass as unsprayed plants; that webworms accounted for this difference in plant fitness was indicated by a significant negative relationship between reproductive effort and an index of webworm damage. Only a handful of metabolites influenced resistance to webworms; these included osthol, sorbitol, and protein in developing fruits as well as previously documented furanocoumarins. Osthol, a coumarinic compound, enhanced resistance, as did protein content, while sorbitol lowered resistance. Other primary metabolites may affect resistance to webworms, but their effect was context-dependent, that is, their effect depended on concentrations of other metabolites (epistasis). Susceptible plant phenotypes were found to have average chemical compositions. Although there was genetic variation in some of the primary metabolites in parsnips, the epistatic nature of their involvement in resistance and the lack of genetic variation in some suggest that selection on them from webworms will be either inconsistent or ineffective.

5-Methoxypsoralen↗
PubMedDate not supplied

[Synthesis of modified psoralen analogues].

Substituted 3-(5-methyl-7-oxofuro[3,2-g]chromen-6-yl)propanoic acids analogous to psoralen were synthesized by linear annulation of a furan moiety to the coumarin system. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 3; see also http://www.maik.ru.

Anthelmintics↗
PubMed2001

Inhibition of rat brain monoamine oxidase activities by psoralen and isopsoralen: implications for the treatment of affective disorders.

Psoralen and isopsoralen, furocoumarins isolated from the plant Psoralea corylifolia L., were demonstrated to exhibit in vitro inhibitory actions on monoamine oxidase (MAO) activities in rat brain mitochondria, preferentially inhibiting MAO-A activity over MAO-B activity. This inhibition of enzyme activities was found to be dose-dependent and reversible. For MAO-A, the IC50 values are 15.2 +/- 1.3 microM psoralen and 9.0 +/- 0.6 microM isopsoralen. For MAO-B, the IC50 values are 61.8 +/- 4.3 microM psoralen and 12.8 +/- 0.5 microM isopsoralen. Lineweaver-Burk transformation of the inhibition data indicates that inhibition by both psoralen and isopsoralen is non-competitive for MAO-A. The Ki values were calculated to be 14.0 microM for psoralen and 6.5 microM for isopsoralen. On the other hand, inhibition by both psoralen and isopsoralen is competitive for MAO-B. The Ki values were calculated to be 58.1 microM for psoralen and 10.8 microM for isopsoralen. These inhibitory actions of psoralen and isopsoralen on rat brain mitochondrial MAO activities are discussed in relation to their toxicities and their potential applications to treat affective disorders.

Affective Disorders, Psychotic↗
PubMed2001

Does the minimal phototoxic dose after 8-methoxypsoralen baths correlate with the individual's skin phototype?

BACKGROUND/AIMS: Up to now no data have been available concerning whether there is a significant correlation between skin phototypes and the minimum phototoxic dose (MPD) after bath water delivery of 8-MOP. METHODS: The skin phototype of each of 46 patients was determined based on the individual past history of solar-induced burning and tanning. In addition, the MPD of each patient was assesed after photosensitization with a warm water bath (37 degrees C, 98.6 degrees F) containing 1.0 mg/l 8-methoxypsoralen (8-MOP). Statistical analysis was performed using a Mann-Whitney U-test and Spearman rank order correlation. RESULTS: The median MPD in patients with skin phototype II was 2.0 J/cm2 (range < or =0.5 to > or =3.5) versus 1.5 J/cm2 (range 1.0 to > or =3.5) in patients with skin phototype III. There was a considerable overlap between both groups. No significant difference was detected comparing both groups (P=0.7326) and Spearman rank order correlation revealed no correlation between skin phototype and MPD. CONCLUSION: Erythemal sensitivity in PUVA bath therapy, measured as MPD, is not correlated with sun-reactive skin phototype in skin types II and III. Thus skin phototype is not a suitable indicator for the initial UVA dose in PUVA bath photochemotherapy.

Data Interpretation, Statistical↗
PubMed2001

PUVA and PUVB in vitiligo--are they equally effective?

BACKGROUND/AIMS: The combination of psoralens with different types of ultraviolet (UVL) sources in the treatment of vitiligo has led to different reports of success. The purpose of this trial is to compare in a random right-left comparison study the efficacy and side effects of oral 8-MOP plus UVA (PUVA) and oral 8-MOP plus UVB (broadband, 290-320 nm P-UVB) in the treatment of vitiligo. METHODS: The study included 24 cases of extensive vitiligo involving more than 30% of the body surface area in a bilateral symmetrical distribution. Each patient received 0.7 mg/kg 8-MOP orally 2 h before the light session. The right side of the body was exposed to UVA (320-400 nm), while the left half was exposed to UVB (290-320 nm). The patients received 3 sessions/week for a total of 30 sessions. RESULTS: Both PUVA and PUVB produced moderate (50-60%) improvement, with similar incidences of phototoxic reaction and skin thickening. However, the study revealed a significant difference in the number of sessions needed to improve produce erythema and perifollicular pigmentation as well as a moderate response, the response on the UVA side always being earlier. Furthermore, the amount of joules needed to achieve the same response was 10 times greater on the UVA side than on the UVB side. CONCLUSION: The use of psoralen plus broadband UVB is as effective as PUVA in the treatment of vitiligo. However, the long-term side effects of psoralen plus UVB are unknown.

Administration, Oral↗
PubMed1998

Targeted gene knockout mediated by triple helix forming oligonucleotides.

Triple helix forming oligonucleotides (TFOs) recognize and bind sequences in duplex DNA and have received considerable attention because of their potential for targeting specific genomic sites. TFOs can deliver DNA reactive reagents to specific sequences in purified chromosomal DNA (ref. 4) and nuclei. However, chromosome targeting in viable cells has not been demonstrated, and in vitro experiments indicate that chromatin structure is incompatible with triplex formation. We have prepared modified TFOs, linked to the DNA-crosslinking reagent psoralen, directed at a site in the Hprt gene. We show that stable Hprt-deficient clones can be recovered following introduction of the TFOs into viable cells and photoactivation of the psoralen. Analysis of 282 clones indicated that 85% contained mutations in the triplex target region. We observed mainly deletions and some insertions. These data indicate that appropriately constructed TFOs can find chromosomal targets, and suggest that the chromatin structure in the target region is more dynamic than predicted by the in vitro experiments.

Animals↗
PubMed1995

Replication of transcriptionally active chromatin.

In eukaryotic cells, active genes and their regulatory sequences are organized into open chromatin conformations in which nucleosomes can be modified, disrupted or totally absent. It has been proposed that these characteristic chromatin structures and their associated factors might be directly inherited by the newly synthesized daughter strands during chromosome duplication. Here we show that in the yeast Saccharomyces cerevisiae, replication machinery entering upstream of a transcriptionally active ribosomal RNA gene generates two newly replicated coding regions regularly packaged into nucleosomes, indicating that the active chromatin structure cannot be directly inherited at the replication fork. Whereas the establishment of an exposed chromatin conformation at some newly replicated rRNA gene promoters can occur shortly after the passage of the replication fork, regeneration of the active chromatin structure along the coding region is always a post-replicative process involving disruption of preformed nucleosomes.

Chromatin↗