Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0920652 (skin irritant)
 188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Release of prostaglandin E2 (PGE2) in cultured peritoneal macrophages of NMRI mice by skin irritant tumor initiators and promoters was investigated. Initiators of the polycyclic aromatic hydrocarbon type, e.g., DMBA, caused slight irritation on the mouse ear but even relatively high doses did not stimulate PGE2-release to any measurable extent within 4 h after administration in vitro. Apparently there is no correlation between irritation and initiating activity in mouse skin and PGE2-release in macrophages. On the other hand, promoters of the diterpene ester type, e.g., TPA, were strong irritants on the mouse ear. Even low doses of these compounds stimulated PGE2-release from macrophages dramatically within 1 h after administration in vitro. Moreover, a good correlation was established between irritant and promoting activity in mouse skin and PGE2-release in macrophages of a series of tigliane, ingenane and daphnane type diterpene derivatives. These results suggest that also in mouse skin PGE2-release may occur following exposure of the target cells to promoters of the diterpene ester type resembling one of the most early molecular events of promotion. This event could initiate both skin irritation and cell proliferation.
 ...
PMID:Inflammatory, tumor initiating and promoting activities of polycyclic aromatic hydrocarbons and diterpene esters in mouse skin as compared with their prostaglandin releasing potency in vitro. 9 35

For investigations of biochemical and molecular mechanism(s) involved in carcinogenesis the three stage initiation/promotion/progression approach in mouse skin provides one of the most developed experimental models. As initiators (and as progressors), solitary carcinogenic polycyclic aromatic hydrocarbons (PAH), such as 7,12-dimethylbenz [a]anthracene (DMBA), are used. As promoters in the last about 15 years, cocarcinogenic skin irritant polyfunctional diterpene esters of plant origin have become most powerful tools. Their low activity "cryptic forms" are activated metabolically by hydrolases yielding highly active skin irritants and cocarcinogens of the "ultimate promoter" type such as the phorbol-12,13-diester TPA and congeners of the ingenane- and daphnane type. In their target cells the ultimate promoters are bound to specific binding sites both through their ester moieties as well as through their diterpene moieties as revealed by structure/activity relationships. In such investigations most recently, also fine structural comparison of threedimensional computergraphs of prototype promoters were included. In correlation with their irritant and promoting activities, diterpene ester promoters exhibit agonist type specific (non-covalent) binding to the particulate fraction of epidermis and other organs or cells. The specifically bound portion of certain electron spin and photoaffinity labeled phorbol ester analogs indicates their distinct molecular orientation in membranes and, in their microenvironment, presence of phospholipids essential for activity of the Ca++ dependent proteinkinase C (PKC). Specific bindings to and activation of PKC was shown for TPA and congeners particularly also in mouse epidermis as one of the target organs of initiation/promotion by DMBA/TPA. Diterpene ester promoters are postulated to interact with the second messenger system operated by inositolphospholipid/diacylglycerol which is linked to (i) receptors of certain (endocrine) hormones or growth factors and (ii) to certain oncogene derived (autocrine) molecular signals. In this way, diterpene ester promoters, mostly taylor-made by partial syntheses, have lead to new dimensions the investigations of specific mechanistic problems of processes of carcinogenesis. Interlinkage of parts of these processes with receptor research opens up new and fascinating aspects of mechanisms of carcinogenesis at the cell and/or molecular level. They will provide important leads in gaining a more differentiated system of assessment of environmental risk factors of cancer for cancer prevention and in developing more purposeful and selective antineoplastic drugs for clinical use.
 ...
PMID:Cell membrane associated protein kinase C as receptor of diterpene ester co-carcinogens of the tumor promoter type and the phenotypic expression of tumors. 300 5

Okadaic acid is a polyether compound of a C38 fatty acid, isolated from a black sponge, Halichondria okadai. Previous studies showed that okadaic acid is a skin irritant and induces ornithine decarboxylase (OrnDCase; 3-hydroxyl-L-glutamate 1-carboxy-lyase, EC 4.1.1.17) in mouse skin 4 hr after its application to the skin. This induction was strongly inhibited by pretreatment of the skin with 13-cis-retinoic acid. A two-stage carcinogenesis experiment in mouse skin initiated by a single application of 100 micrograms of 7,12-dimethylbenz[a]anthracene (DMBA) and followed by application of 10 micrograms of okadaic acid twice a week revealed that okadaic acid is a potent additional tumor promoter: tumors developed in 93% of the mice treated with DMBA and okadaic acid by week 16. In contrast, tumors were found in only one mouse each in the groups treated with DMBA alone or okadaic acid alone. An average of 2.6 tumors per mouse was found in week 30 in the group treated with DMBA and okadaic acid. Unlike phorbol 12-tetradecanoate 13-acetate (TPA), teleocidin, and aplysiatoxin, okadaic acid did not inhibit the specific binding of [3H]TPA to a mouse skin particulate fraction when added up to 100 microM or activate calcium-activated, phospholipid-dependent protein kinase (protein kinase C) in vitro when added up to 1.2 microM. Therefore, the actions of okadaic acid and phorbol ester may be mediated in different ways. These results show that okadaic acid is a non-TPA-type tumor promoter in mouse skin carcinogenesis.
 ...
PMID:Okadaic acid: an additional non-phorbol-12-tetradecanoate-13-acetate-type tumor promoter. 312 94

To provide guidelines for handling the very labile phorbol ester, RPA,2 its stability under various laboratory conditions was studied. RPA will remain undecomposed for 8 weeks if stock solutions are made in ethanol, ethyl acetate, or DMSO and stored in absolute darkness at -20 degrees C. When exposed to light RPA readily isomerizes to 13'-cis-RPA. Structure/activity investigations of irritant polyfunctional diterpene esters of phorbol, ingenol, and resiniferonol with saturated and unsaturated aliphatic or with aromatic acids indicate that their irritant activity is a necessary, yet insufficient prerequisite for initiation- (or tumor-) promoting activity (e.g., Refs. 3 and 4). For further testing of this hypothesis, the retinoic acid analogue of the mouse skin irritant and initiation-promoter TPA, i.e., RPA, was designed (7). In initiation/promotion experiments of skin of NMRI mice, it proved to be an irritant almost as active as TPA, but only marginally active as a promoter. In combination with TPA, it turned out to be a "second stage" promoter (PII-promoter) (1, 6) in our strain of mice (2, 7). RPA is a much more labile compound than TPA (5), especially in the solid form. If stored in solution, special precautions have to be taken to ascertain that the concentration or dose intended is represented by undecomposed RPA.
 ...
PMID:Stability of the "second stage" promoter 12-O-retinoylphorbol-13-acetate. 398 82

Contact dermatitis produces an inflammatory reaction primarily via stimulation of keratinocytes and cells of the immune system, which promote the release of cytokines, reactive oxygen species (ROS), and other chemical mediators. Eugenol (EUG, phenylpropanoid of essential oils) has attracted attention due to its anti-inflammatory properties, as well as antioxidant effect. On the other hand, it is volatile and insoluble and is a skin irritant. In this case, nanostructured systems have been successfully employed as a drug carrier for skin diseases since they improve both biological and pharmaceutical properties of active compounds. The cytotoxic, antioxidant, and anti-inflammatory effects of EUG were assessed in human neutrophils and keratinocytes. Additionally, polymeric nanocarries (NCEUG) were prepared to improve the chemical and irritant characteristics of EUG. EUG presented apparent safety and antioxidant and anti-inflammatory effects on human neutrophils, but presented cytotoxic effects on keratinocytes. However, the nanocapsules were able to reduce its cytotoxicity. An in vivo experiment of irritant contact dermatitis (ICD) in mice induced by TPA showed that NCEUG reduced significantly the ear edema in mice when compared to the EUG solution, as well as the leukocyte infiltration and IL-6 level, possibly due to better skin permeation and irritancy blockage. These findings suggest that EUG is a promising bioactive molecule, and its nanoencapsulation seems to be an interesting approach for the treatment of ICD.
 ...
PMID:Eugenol as a Promising Molecule for the Treatment of Dermatitis: Antioxidant and Anti-inflammatory Activities and Its Nanoformulation. 3064 16