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2.
Chem Res Toxicol ; 9(4): 729-36, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8831817

ABSTRACT

Several naturally occurring coumarins contained in the human diet have been found to be effective inhibitors and inactivators of murine hepatic ethoxyresorufin O-dealkylase (EROD) and pentoxyresorufin O-dealkylase in vitro [Cai, Y., Bennett, D., Nair, R.V., Ceska, O., Ashwood-Smith, M., and DiGiovanni, J. (1993) Chem. Res. Toxicol. 6, 872-879]. In the present study, these same coumarins decreased the content of cytochrome P450 (P450) in either 3-methylcholanthrene (MC)- or phenobarbital-induced murine hepatic microsomes but did not have a major effect on heme content. Detailed in vitro studies with [14C]coriandrin, which selectively inhibits and inactivates P450 1A1-mediated EROD activity, demonstrated that it covalently bound, in a preferential manner, to hepatic microsomal protein from MC-pretreated mice. A linear relationship was observed between covalent binding and loss of EROD activity. The inclusion of electrophile trapping agents in the incubations significantly inhibited the covalent binding of [14C]coriandrin to microsomal protein. In addition, the covalent binding of [14C]coriandrin was decreased 46% by 7,8-benzoflavone (7,8-BF), 58% by a monoclonal antibody with specificity toward MC-induced form(s) of P450, and 60% by ethoxyresorufin, implicating the bioactivation of coriandrin by P450 1A1. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of [14C]coriandrin-bound microsomal protein from MC-pretreated mice showed that [14C]coriandrin bound covalently to a protein with an approximate molecular mass of 49 kDa. Again, addition of 7,8-BF or polyclonal antibody against P450 1A1 reduced the covalent binding of [14C]coriandrin to this specific protein band. Interestingly, coriandrin was also found to be a potent inhibitor and inactivator of purified human P450 1A1. These results demonstrate that certain coumarins to which humans are exposed in the diet are bioactivated by P450 1A1 to reactive intermediates that subsequently form covalent adducts with the apoprotein, effectively destroying enzyme activity. Thus, certain naturally occurring coumarins may have a significant effect on human health.


Subject(s)
Coumarins/pharmacology , Cytochrome P-450 CYP1A1/metabolism , Enzyme Inhibitors/pharmacology , Furocoumarins/pharmacology , Microsomes, Liver/drug effects , Animals , Anticoagulants/chemistry , Anticoagulants/metabolism , Anticoagulants/pharmacology , Anticonvulsants/pharmacology , Carbon Radioisotopes , Carcinogens/pharmacology , Chromatography, High Pressure Liquid , Coumarins/chemistry , Coumarins/metabolism , Cytochrome P-450 CYP1A1/antagonists & inhibitors , Electrophoresis, Polyacrylamide Gel , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Female , Furocoumarins/chemistry , Furocoumarins/metabolism , Heme/analysis , Humans , Hypnotics and Sedatives/pharmacology , Methylcholanthrene/pharmacology , Mice , Mice, Inbred SENCAR , Microsomes, Liver/enzymology , Phenobarbital/pharmacology , Plant Extracts/chemistry , Plant Extracts/metabolism , Plant Extracts/pharmacology , Radioligand Assay
3.
Mol Hum Reprod ; 2(1): 46-51, 1996 Jan.
Article in English | MEDLINE | ID: mdl-9238657

ABSTRACT

Experimental evidence in a number of different in vivo and in vitro systems indicates clearly that the vertebrate oocyte is capable of repairing endogenous and exogenous DNA damaged as a result of meiotic recombination, the action of UV and X-irradiation or the effects of mutagenic chemicals. It would appear that both before and after the dictyate stage of meiosis the oocyte has less repair capacity and/or is more sensitive to DNA damaging agents. Epigenetic factors associated with the expression of genetic faults arising in oocytes have been largely ignored in the past. It is probable that attention to such factors, will in the future, lead to a better appreciation of the capacity of oocytes to repair genetic damage. Non-disjunctional events are particularly prone to occur in dictyate oocytes. Oxygen deprivation, perturbations of microtubular structure by temperature and other factors appear to have disastrous cytogenetic consequences at this otherwise resistant resting stage.


Subject(s)
DNA Repair , Oocytes/cytology , Animals , DNA Damage , Humans , Meiosis , Oocytes/chemistry , Zygote/chemistry , Zygote/cytology
4.
Hum Reprod ; 10(12): 3082, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8822415
7.
Can J Public Health ; 86(1): 51-6, 1995.
Article in English | MEDLINE | ID: mdl-7728718

ABSTRACT

The rationale and approach are presented that were used to investigate the Powell River RCMP detachment building, perceived to have a higher than normal cancer incidence and whose occupants demanded to know whether the building was safe to work in. On the basis of the history of the building and the cancers observed, a set of carcinogens were looked for in areas where the worst conditions were expected. A positive result would initiate a second more in-depth survey. This was done for Fyrol-PCF, which was shown to be a contaminant of the charcoal adsorption tubes used. The results of the survey indicated a safe work environment. The chemical analyses, complemented by the bioassay and comparison with a recognizable control site, were found to be most effective in the acceptance of the results by the public. The conclusions from this survey were confirmed by the findings of an epidemiological survey.


Subject(s)
Air Pollution, Indoor/analysis , Environmental Monitoring , Neoplasms/etiology , Occupational Diseases/etiology , Police , Air Pollution, Indoor/adverse effects , British Columbia , Case-Control Studies , Environmental Monitoring/methods , Humans , Incidence , Space-Time Clustering
9.
Chem Res Toxicol ; 6(6): 872-9, 1993.
Article in English | MEDLINE | ID: mdl-8117927

ABSTRACT

The present study was designed to evaluate the effects of a series of natural coumarins on ethoxyresorufin O-dealkylase (EROD) and pentoxyresorufin O-dealkylase (PROD) activities in vitro using hepatic tissues from SENCAR mice. Fifteen different coumarins were examined for potential modulating activities. Several naturally occurring coumarins, found in the human diet, were effective inhibitors of hepatic EROD activity in vitro, including coriandrin, bergamottin, isoimperatorin, and ostruthin. Notably, coriandrin and bergamottin were approximately as potent as 7,8-benzoflavone, a relatively selective inhibitor of cytochrome P450 1A1. Several naturally occurring coumarins were also potent inhibitors of hepatic PROD activity, including imperatorin, bergamottin, isopimpinellin, and angelicin. Kinetic studies of the type of inhibition revealed that these compounds inhibited hepatic EROD and PROD activity by a variety of modes rather than by a uniform one. Furthermore, experiments using a two-stage incubation assay revealed that coriandrin, imperatorin, ostruthin, and several other natural coumarins inactivated hepatic EROD activity (i.e., predominantly cytochrome P450 1A1-mediated) and that isopimpinellin inactivated hepatic PROD activity (i.e., predominantly cytochrome P450 2B1-mediated). Finally, the results indicate that some coumarins had selective inhibitory effects for EROD vs PROD and preliminary analyses suggested a possible structural basis for the observed differences. The current data suggest that certain naturally occurring coumarins, to which humans are exposed in the diet, are potent modulators of cytochrome P450. Furthermore, these compounds may be capable of influencing the metabolic activation of other xenobiotics, including chemical carcinogens.


Subject(s)
Coumarins/pharmacology , Cytochrome P-450 Enzyme Inhibitors , Microsomes, Liver/enzymology , Oxidoreductases/antagonists & inhibitors , Animals , Cytochrome P-450 CYP1A1 , Cytochrome P-450 CYP2B1 , Diet , Enzyme Activation/drug effects , Female , Kinetics , Mice , Mice, Inbred Strains , Microsomes, Liver/drug effects
10.
Photochem Photobiol ; 57(3): 491-6, 1993 Mar.
Article in English | MEDLINE | ID: mdl-8475184

ABSTRACT

The novel furoisocoumarin, coriandrin, which was found recently to possess an interesting combination of photobiological properties, was investigated for antiviral activity in the presence and absence of UVA (long-wavelength ultraviolet radiation). In contrast to results obtained with other antiviral furocoumarins, such as 8-MOP (8-methoxypsoralen), coriandrin was much more phototoxic to the RNA-virus Sindbis virus than to the DNA-virus murine cytomegalovirus, although both viruses were substantially more sensitive to this compound than they were to 8-MOP. Human immunodeficiency virus, HIV-1, was also susceptible to coriandrin + UVA. Another unexpected finding was that viruses without membranes were completely resistant to coriandrin. This suggests that a membrane component was a target for the compound. The antiviral activity of coriadrin was profoundly inhibited by serum components in the reaction mixtures, which suggests that the compound may have a strong affinity for certain protein or lipid materials, although maximal interference was only obtained when all components of the reaction mixture, virus, coriandrin and serum, were irradiated simultaneously. Thus it appears that coriandrin has unusual antiviral properties that would not be predicted from its chemical similarity to furocoumarins.


Subject(s)
Antiviral Agents/pharmacology , Furocoumarins/pharmacology , HIV-1/drug effects , Radiation-Sensitizing Agents/pharmacology , Ultraviolet Rays , Viruses/drug effects , 3T3 Cells , Animals , Cell Line , Furocoumarins/chemistry , HIV-1/radiation effects , Humans , Methoxsalen/chemistry , Methoxsalen/pharmacology , Mice , Molecular Structure , Vero Cells , Viruses/radiation effects
12.
Photochem Photobiol ; 55(4): 529-32, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1620730

ABSTRACT

5-geranoxypsoralen (Bergamottin) does not photosensitize bacteria or a bacterial virus. It does, however, photosensitize mammalian cells in tissue culture. Irradiation with either black light (300-400 nm) or fluorescent ceiling lights produced at least four photobiologically active degradation products, the chemical nature of which still remains to be elucidated. Prolonged exposure to black light resulted in the formation of inactive molecule(s).


Subject(s)
Cell Survival/drug effects , Escherichia coli/drug effects , Furocoumarins/pharmacology , Methoxsalen/pharmacology , Radiation-Sensitizing Agents/pharmacology , T-Phages/drug effects , Animals , CHO Cells , Cell Survival/radiation effects , Cricetinae , Escherichia coli/genetics , Escherichia coli/radiation effects , Frameshift Mutation , Furocoumarins/radiation effects , Photolysis , T-Phages/radiation effects
13.
Photochem Photobiol ; 50(6): 745-51, 1989 Dec.
Article in English | MEDLINE | ID: mdl-2696989

ABSTRACT

The photobiological properties of a novel, naturally occurring furoisocoumarin isolated from coriander and named coriandrin are described. Photosensitized lethal and mutagenic effects in bacteria indicate that it is more active than psoralen. It is a weak frameshift mutagen in the dark. Mammalian cells in tissue culture are photosensitized more actively with coriandrin than with psoralen even though preliminary evidence from interrupted radiation experiments and DNA analysis suggest that coriandrin does not form DNA interstrand crosslinks. Sister chromatid exchanges were induced with a unit dose of 1.1 x 10(-2) with coriandrin; the value for psoralen is 3 x 10(-3). Coriandrin appears to be metabolized more rapidly than furocoumarins by liver mixed function oxidases. Skin photosensitizing activity is very weak compared with psoralen, a surprising observation considering its potency in biological test systems.


Subject(s)
DNA/drug effects , Furocoumarins/pharmacology , Radiation-Sensitizing Agents/pharmacology , Skin/drug effects , Ultraviolet Rays , Animals , Cell Line , DNA/radiation effects , DNA, Ribosomal/drug effects , DNA, Ribosomal/radiation effects , Escherichia coli/drug effects , Escherichia coli/genetics , Escherichia coli/radiation effects , Furocoumarins/isolation & purification , Humans , Magnoliopsida , Mutation , Plasmids , Sister Chromatid Exchange/drug effects , Sister Chromatid Exchange/radiation effects , Skin/radiation effects , Xenopus
14.
Hum Reprod ; 4(6): 702-5, 1989 Aug.
Article in English | MEDLINE | ID: mdl-2778056

ABSTRACT

Human serum and Albuminar 5 (A5) were compared as medium supplements to Earle's solution containing pyruvate in clinical IVF. One-hundred patients in each group showed a fertilization rate of 60% with serum and of 62% with A5. The overall pregnancy rates in the serum and A5 groups were 20 and 24%, respectively. The incidence of failed fertilization (6-7%) and of multipronucleate oocytes (4-5%) was similar in both groups. At 37 degrees C, sperm survived less well in A5 although the rate of fertilization was not reduced. Blastocyst formation was not seen in 'spare' embryos grown in vitro in medium containing 15% v/v A5.


Subject(s)
Caprylates , Fertilization in Vitro , Serum Albumin , Tryptophan/analogs & derivatives , Female , Humans , Male
15.
Hum Reprod ; 3(6): 795-802, 1988 Aug.
Article in English | MEDLINE | ID: mdl-3220945

ABSTRACT

Observations made during the freezing and thawing of mouse and human oocytes and mouse embryos with the cryomicroscope suggest that physical factors as well as physicochemical factors may play a role in the development of lethal damage upon thawing. The point of contact with the approaching ice front may predispose that area to the appearance of future cytoplasmic blebbing. The ice front distorts the oocyte and this distortion remains during its subsequent thermal history and is unrelated to desiccation distortion. Ice initiates the formation of both intra- and extracellular gas bubbles which are apparent upon thawing; with the progression of the thawing process they can be seen to grow in volume. Growth of these bubbles can give rise to expanding vesicles which can totally destroy an embryo. The consequences of these physical factors for the successful cryopreservation of oocytes, embryos, tissues and organs are discussed.


Subject(s)
Embryology , Oocytes , Tissue Preservation , Animals , Cell Survival , Female , Freezing , Humans , Male , Mice , Mice, Inbred Strains , Pregnancy
16.
J Cancer Res Clin Oncol ; 114(5): 523-4, 1988.
Article in English | MEDLINE | ID: mdl-2846583

ABSTRACT

Organized tissue fragments obtained by dissociation of a pure mucoid carcinoma of the breast were cultured in vitro. The cellular organization of the fragments appears similar to that observed in vivo, and consist of mucous-filled spherules surrounded by a single layer of tumour cells. Time-lapse video recordings revealed that the cells surrounding these fragments undergo a concerted contraction and relaxation over the time span of several hours. The presence of cytokeratin and oestrogen receptors in the cells suggests an epithelial derivation. Movement of tumour fragments of the type described here could potentially influence the metastatic process of some breast cancers.


Subject(s)
Adenocarcinoma, Mucinous/pathology , Breast Neoplasms/pathology , Female , Humans , Tumor Cells, Cultured
18.
Planta Med ; (6): 462-4, 1986 Dec.
Article in English | MEDLINE | ID: mdl-17345409

ABSTRACT

Fresh parsley leaves and roots were analyzed by HPLC and photobiological assay for photoactive furocoumarins. Oxypeucedanin ( 7), not previously reported from parsley, was found to be the major component (70-100 ppm wet weight). Although only moderately photoactive, its high concentration in parsley may be partially responsible for contact photodermatitis. Other photoactive compounds, namely 5-MOP ( 2), 8-MOP ( 3), psoralen ( 1), isopimpinellin ( 4) and imperatorin ( 5) were also present and quantified.

20.
Hum Reprod ; 1(3): 181-2, 1986 Apr.
Article in English | MEDLINE | ID: mdl-3624425

ABSTRACT

Normal levels of pyruvate in freshly collected follicular fluid were found to be 0.45 mM, a value approximately 4 X that of serum. The utilization of pyruvate by human oocytes and early embryos has been measured, non-invasively, using two similar but separate analytical methods. The mature oocyte has a high level of pyruvate uptake (36 pmol/embryo/h). After fertilization this value falls, and then slowly increases to reach a peak just prior to the morula stage of 27 pmol/embryo/h before decreasing. Degenerating oocytes and embryos demonstrated much lower pyruvate uptake rates. The possible usefulness of this method for assessing embryo viability is discussed.


Subject(s)
Blastocyst/metabolism , Pyruvates/metabolism , Spectrometry, Fluorescence/methods , Humans , Morula/metabolism , Oocytes/metabolism
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