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Abstract: Introduction: Polymorphisms in CYP2C9 can vary the rate of metabolic clearance of oral anticoagulants, risking toxicity in patients. The present study focused on exploring the genetic etiology of idiopathic hyper sensitivity to coumarin anticoagulants in a patient who presented with multiple bleeding episodes and supra-elevated International Normalized Ratios. Materials and Methods: Bidirectional gene sequencing of CYP2C9 and VKORC1 was carried out. Using allele-specific polymerase chain reaction, the identified novel variant was genotyped in 309 patients on anticoagulation therapy. The pharmacoproteomic significance of the novel genetic variant was elucidated by structural demonstration of binding of coumarin molecules within the mutant CYP2C9 204His protein model and in silico bioinformatic evolutionary analyses. Three-dimensional structure model of the mutant protein was constructed on the basis of the published X-ray crystal structure of human CYP2C9 protein (Protein Data Bank, 1R9O). Results: The patient was identified to have a novel heterozygous missense mutation in exon 4 of CYP2C9 gene (g.9172A>C; p.Asn204His; CYP2C9*57). The variant was absent in the 309 genotyped patients. In silico bioinformatic analyses indicated the variant to have a deleterious effect on the protein. Analysis of 3D structure model of the mutant protein revealed that the substituted His204 led to restricted binding of the coumarin drug within the binding site of CYP2C9 enzyme, thereby inhibiting its metabolic clearance and thus explaining the enhanced pharmacologic effect and bleeding in the patient. Conclusions: The study elucidates the structurally deleterious role of the novel CYP2C9*57 missense mutation in coumarin toxicity. [Copyright &y& Elsevier]

This study was undertaken to investigate the effect of 4-arylcoumarin (5,7-dimethoxy-4-p-methoxyphenylcoumarin; MPC) on immediate-type allergic reaction and inflammatory cytokine secretion. MPC inhibited compound 48/80-induced systemic reactions in mice. When MPC was given as a pretreatment at concentrations ranging from 0.001 to 1 g/kg, the serum histamine levels induced by compound 48/80 were reduced in a dose-dependent manner. In addition, MPC also inhibited the passive cutaneous anaphylaxis activated by anti-dinitrophenyl (DNP) IgE antibody dose dependently. Furthermore, MPC decreased the phorbol 12-myristate 13-acetate plus calcium ionophore A23187-stimulated tumor necrosis factor-α and interleukin-6 secretion in human mast cells. These results indicate that MPC may be beneficial in the treatment of immediate-type allergic reactions. [ABSTRACT FROM AUTHOR]

Background/Aims: Positive patch tests are considered representative of a contact allergy to the tested chemical. However, contaminants and derivatives rather than the suspected chemical itself could be responsible for the allergic skin reactions. Here, we tested the importance of contaminants in the sensitizing and allergenic properties of coumarin in mice and humans. Coumarin, an ingredient in cosmetics and fragrances, was chosen as the reference chemical since conflicting results have been obtained regarding its ability to induce contact allergy. In some chemical preparations, this could be explained by the presence of coumarin derivatives endowed with allergenic properties. Methods: In mice, three different coumarin preparations were tested in the local lymph node assay. In humans, we assessed the irritant and allergenic properties of highly pure coumarin in nonallergic and fragrance-allergic patients. Results: Pure coumarin did not exhibit irritant or sensitizing properties in the local lymph node assay. In contrast, two other commercially available coumarins and three contaminants that were detected in these coumarin preparations were identified as weak and moderate sensitizers, respectively. In humans, pure coumarin was extremely well tolerated since only 1 out of 512 patients exhibited a positive patch test to the chemical. Conclusions: These results indicate that coumarin cannot be considered as a common contact allergen and further emphasize that purity of chemicals is mandatory for the assessment of their allergenicity. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A case of acquired photocontact allergy to furocumarins in plants is reported. Photopatch testing was performed with Four psoralens [8-methoxypsoralen 8-MOP), 5-methoxypsoralens (5-MOP). trimethylpsoralen (TMP) and imperatorin (IMP)]. The use of serial dilutions of the test compounds made it possible to differentiate between photoallergic and phototoxic reactions. 8-MOP gave a positive eczematous test reaction down to a concentration of 0.0001 %. The reactions to 5-MOP and IMP also were positive, while that to IMP was negative. Histopathological examination of a biopsy specimen from a positive test site showed changes consistent with photoallergic contact dermatitis. The multiple reactions could be explained on the basis of multiple sensitization. but cross reactions cannot be ruled out. [ABSTRACT FROM AUTHOR]

5 coumarins used in perfumery, cosmetics, therapeutic ointments or occurring naturally were investigated by Freund's complete adjuvant technique (FCAT) in guinea pigs to determine their contact sensitizing potency. 4-methylesculetin was also studied. Esculetin, dihydrocoumarin and daphnetin were found to be moderate to strong sensitizers, while fraxetin was nearly and 7-methylcoumarin completely inactive. The results corroborate the hypothetical view that only those coumarins having a catecholic disubstitution in the benzene ring, e.g., esculetin, 4-methylesculetin, daphnetin, can become sensitizers on the basis that they are capable of forming ortho-quinones under oxidizing conditions. [ABSTRACT FROM AUTHOR]