PURPOSE: To discuss the contribution of psoralen and bergapten metabolites on psoralens toxicity. METHODS: Computational chemistry prediction of metabolic reactions and toxicophoric groups based on the expert systems Derek and Meteor. RESULTS: a total of 15 metabolites were suggested for both psoralen and bergapten based on phase 1 and 2 biotransformations until the 3rd generation. Five toxicophoric substructures were shared among psoralen, bergapten and their corresponding metabolites; one toxicophoric marker (resorcinol) was only identified in bergapten and its biotransformation products. CONCLUSION: Although the toxic effects of psoralens are well known and documented, there is little information concerning the role of their metabolites in this process. We believe this work add to the knowledge of which molecular substructures are relevant to the process of metabolism and toxicity induction, thus guiding the search and development of more effective and less toxic drugs to treat vitiligo.
A number of studies have demonstrated that cytochrome P450 (P450) converts furanocoumarin derivatives into reactive molecules, which form covalent bonds to biomolecules. 5-Methoxypsoralen (5-MOP) is a natural furanocoumarin from apiaceous plants. In this study, we examined the effect on 5-MOP metabolism of single nucleotide polymorphisms (SNPs) in CYP2A13. We used Escherichia coli-generated recombinant enzymes of wild-type CYP2A13*1 and five variants, CYP2A13*4 (R101Q), CYP2A13*5 (F453Y), CYP2A13*6 (R494C), CYP2A13*8 (D158E), and CYP2A13*9 (V323L). In high-performance liquid chromatography analyses of 5-MOP metabolic products, CYP2A13*1 converted 5-MOP into 5-MOP dihydrodiol; K(m) and V(max) values of the reaction were 1.44 +/- 0.17 uM and 4.23 +/- 0.36 nmol/(min x nmol P450), respectively. The generation of a dihydrodiol from 5-MOP implies that conversion by CYP2A13 causes toxicity due to the formation of covalent bonds with DNA or proteins. Most of the CYP2A13 variants could metabolize 5-MOP; K(m) values for CYP2A13*5, *6, *8, and *9 were 1.63 =/- 0.12, 1.36 +/- 0.10, 0.85 +/- 0.09, and 0.58 +/- 0.06 uM, respectively, and V(max) values were 3.20 +/- 0.13, 4.69 +/- 0.13, 2.34 +/- 0.07, and 1.84 +/- 0.09 nmol/(min x nmol P450), respectively. However, the processing of 5-MOP by CYP2A13*4 was not detectable. Based on this data, we hypothesize that SNPs within the CYP2A13 gene affect metabolism of 5-MOP in humans.
来源:Hazardous Substances Data Bank (HSDB)
代谢
山梗菜苷已知的人类代谢物包括Unii-3abk64HG9O。
Bergapten has known human metabolites that include Unii-3abk64HG9O.
IDENTIFICATION AND USE: 5-Methoxypsoralen (5-MOP) is a furocoumarin. As a component of bergamot oil, 5-MOP is present in some perfumes and fragrances, sunscreen preparations and food products. It has been used to promote tanning in suntan preparations. 5-MOP, in combination with UVA, is commonly used as a photochemotherapeutic agent for the treatment of psoriasis. HUMAN STUDIES: Photochemotherapy is very effective for the treatment of skin diseases such as psoriasis, as well as for the prophylactic 'hardening' therapy of patients suffering from polymorphic light eruption. The photosensitizers most widely used for oral photochemotherapy are the furocoumarins. Beside light-induced phototoxic reactions due to the photosensitizing activity of psoralens, side-effects after the oral intake of psoralens are nausea and vomiting, headaches, anxiety and sleeplessness. Anaphylaxis to 5-MOP has been reported. A 55-year-old woman with psoriasis vulgaris was treated with oral 5-MOP and UVA photochemotherapy. After 40 treatments over 3 months she became unwell with hepatitis attributable to the psoralen. 5-MOP caused chromosomal damage in human cells in vitro. ANIMAL STUDIES: When 5-MOP was given orally to beagle dogs at daily doses of 100 or 400 mg/kg (8 days), 60 mg/kg (28 days) or 48 mg/kg (26 wk), at the highest doses tested there were delayed signs of behavioral toxicity, bullous dermatitis, bilateral keratitis, decreased food consumption and decreased weight gain. The cutaneous lesions were reversible, whereas the ocular lesions were not. Hepatomegaly, necrosis and hepatic inflammation occurred in the 48-mg/kg dose group. 5-MOP plus UVA and 12-O-tetradecanoylphorbol 13-acetate induced skin carcinomas in mice. Rats were dosed daily with 5-MOP (75 or 150 mg/kg, p.o.), or vehicle control. Treated males had significantly smaller pituitary glands, fewer sperm per ejaculate, and fewer sperm in the vasa deferentia and epididymides than controls. Dosing significantly elevated levels of testosterone and increased relative testis weight, but did not directly affect testicular weight. Females bred to dosed males required more time to become pregnant, and these males required more breeding attempts. Female rabbits were given 5-MOP orally at daily doses of 0, 70 or 560 mg/kg bw on days 7-18 of gestation. With 560 mg/kg, there was maternal toxicity and a dose-dependent increase in fetal abnormalities. 5-MOP formed a noncovalently-bound complex with DNA in vitro in the dark. It photobound covalently to DNA in vitro in Saccharomyces cerevisiae and in Chinese hamster V79 cells. It photoinduced interstrand cross-links in DNA in vitro and in Chinese hamster V79 cells. 5-MOP alone was reported to be mutagenic to Salmonella typhimurium TA100 in the presence or absence of metabolic activation and to Escherichia coli lac- z (ND160). 5-MOP plus UVA reduced survival of repair-deficient mutants of Bacillus subtilis and E. coli, addition of metabolic activator inhibited the lethal activity.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
人类致癌性证据不足。动物致癌性证据充分。总体评估：2A组：该物质很可能对人类致癌。
Inadequate evidence of carcinogenicity in humans. Sufficient evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 2A: The agent is probably carcinogenic to humans.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
国际癌症研究机构致癌物：5-甲氧基补骨脂素
IARC Carcinogenic Agent:5-Methoxypsoralen
来源:International Agency for Research on Cancer (IARC)
毒理性
致癌物分类
国际癌症研究机构（IARC）致癌物分类：2A组：可能对人类致癌
IARC Carcinogenic Classes:Group 2A: Probably carcinogenic to humans
来源:International Agency for Research on Cancer (IARC)
毒理性
致癌物分类
国际癌症研究机构专论：第40卷：（1986年）一些天然存在和合成的食品成分，呋喃香豆素和紫外线辐射
IARC Monographs:Volume 40: (1986) Some Naturally Occurring and Synthetic Food Components, Furocoumarins and Ultraviolet Radiation
来源:International Agency for Research on Cancer (IARC)
Micronized bergapten in capsules was absorbed slowly by volunteers (time to max serum concn 3.2 hr; elim half-time about 1 hr). When injected iv into rabbits, elim half-time 1-2 min (alpha-phase) & 15 min (beta-phase).
5-Methoxypsoralen showed a high binding affinity to serum proteins & 98-99% was protein bound. Its high binding affinity resulted in higher tissue concn. In the epidermis, it appeared to be bound to independent & noninteracting sites.
Enrichment in epidermis of 5-methoxypsoralen was measured. It was concentrated by human epidermis & concn reached within the tissue was 10-500 times higher than concn of substance in surrounding buffer. The partitioning distribution among tissue components could account for its behavior.
In young adult Hartley guinea-pigs, a linear relation was found between serum and epidermal concn of 5-methoxypsoralen, and the observed skin phototoxicity correlated with the serum 5-methoxypsoralen concn ... .
An efficient synthesis of the linear furanocoumarin, bergapten, is reported. In order to avoid the formation of the angular furanocoumarin, we have adopted iodine as protecting group at the 8 position of the coumarin ring.
METHOD OF IMPROVING STABILITY OF SWEET ENHANCER AND COMPOSITION CONTAINING STABILIZED SWEET ENHANCER
申请人：TACHDJIAN Catherine
公开号：US20120041078A1
公开（公告）日：2012-02-16
The present invention includes methods of stabilizing one or more sweet enhancers when they are exposed to a light source as well as liquid compositions containing one or more sweet enhancers and one or more photostabilizers.
[EN] COMPOUNDS ACTIVE TOWARDS NUCLEAR RECEPTORS<br/>[FR] COMPOSÉS ACTIFS VIS-À-VIS DES RÉCEPTEURS NUCLÉAIRES
申请人：NUEVOLUTION AS
公开号：WO2021124279A1
公开（公告）日：2021-06-24
Disclosed are compounds active towards nuclear receptors, pharmaceutical compositions containing the compounds and use of the compounds in therapy.
揭示了对核受体活性的化合物，包含这些化合物的药物组合物以及这些化合物在治疗中的用途。
[EN] PYRAZOLO [4, 3-D] PYRIMIDINES USEFUL AS KINASE INHIBITORS<br/>[FR] PYRAZOLO[4,3-D]PYRIMIDINES UTILES EN TANT QU'INHIBITEURS DE KINASES
申请人：ORIGENIS GMBH
公开号：WO2012143144A1
公开（公告）日：2012-10-26
The present invention relates to novel compounds of formula (I) that are capable of inhibiting one or more kinases, especially SYK (Spleen Tyrosine Kinase), LRRK2 (Leucine-rich repeat kinase 2) and/or MYLK (Myosin light chain kinase) or mutants thereof. The compounds find applications in the treatment of a variety of diseases. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, alzheimer's disease, parkinson's disease, skin disorders, eye diseases, infectious diseases and hormone-related diseases.
[EN] HETEROCYCLIC COMPOUNDS AS KINASE INHIBITORS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES EN TANT QU'INHIBITEURS DE KINASES
申请人：ORIGENIS GMBH
公开号：WO2012143143A1
公开（公告）日：2012-10-26
The present invention relates to novel compounds of formula (I) that are capable of inhibiting one or more kinases, especially SYK (Spleen Tyrosine Kinase), LRRK2 (Leucine-rich repeat kinase 2) and/or MYLK (Myosin light chain kinase) or mutants thereof. The compounds find applications in the treatment of a variety of diseases. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, alzheimer's disease, parkinson's disease, skin disorders, eye diseases, infectious diseases and hormone-related diseases.
Compounds I and II, as well as prodrugs, hydrates, solvates, N-oxides, salts and pharmaceutical compositions containing them, are useful for treating vitiligo. In certain embodiments, the compounds are provided in topical compositions.
