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Varfarin (4-OH kumarin) je antikoagulant prve generacije koji je u upotrebi kao lek i rodenticid. Osnovni biološki efekat ostvaruje inhibicijom vitamin K-zavisnog puta u kompletnoj sintezi brojnih faktora koagulacije u jetri. Varfarin deluje i na druge proteine za čiju je biološku aktivnost neophodan vitamin K, kao što su proteini uključeni u proces rasta, kalcifikacije kostiju, proliferacije mezangijskih ćelija, i proteine uključene u prenos ćelijskih signala. Širokom upotrebom varfarina kao leka i kao rodenticida uočeni su njegovi brojni neželjeni efekti. U terapijskim dozama on može da uzrokuje akutna i hronična neželjena dejstva, kao što su nekroza kože i kalcifikacija zida arterija, a osim antikoagulantnog može da ima i proinflamatorno i antiinflamatorno sistemsko dejstvo. Nepravilno rukovanje u proizvodnji i upotrebi varfarina kao rodetnicida može dovesti do jednokratne ili ponavljane inhalacione, oralne ili perkutane ekspozicije. Kontakt kože sa antikoagulantnim rodenticidima može da uzrokuje perkutanu intoksikaciju sa razvojem koagulopatije i krvarenja čak do smrtnog ishoda i lokalnu iritaciju kože. Poseban problem predstavlja neprepoznata izloženost malim dozama varfarina čiji se efekti mogu manifestovati i kao simptomi nepoznate bolesti i tada se varfarin može posmatrati i kao ksenobiotik. U našim eksperimentalnim istraživanjima opredelili smo se za ispitivanje ksenobiotičkih efekata varfarina u koži, s obzirom da je ona čest put ekspozicije, a ovakvi njegovi efekti nisu poznati U početnim istraživanjima utvrdili smo da epikutano aplikovan varfarin pokazuje lokalni i sistemski proinflamatorni, prooksidativni i imunomodulatorni efekat, a zavisno od aplikovane doze i direktan imunotoksični i dermatotoksični efekat. Preliminarna histomorfološka analiza je pokazala promene u koži koje mogu, sa jedne strane, da odražavaju inflamatorno-reparatorni program, ali, sa druge, da predstavljaju uvod u patološke događaje u koži. U ovom istraživanju ispitan je efekat jednokratne lokalne epikutane aplikacije varfarina na koži kod Dark Agouty pacova u dozama od 1μg, 10μg i 100μg. Analizirana je sedmodnevna dinamika selektivnih funkcionalnih parametara oksidativnog stresa, promena u imunskom sistemu, mikrovaskulaturi, ćelijskom ciklusu keratinocita i dermalnih fibroblasta i strukturne promene u koži histohemijskim, imunohistohemijskim metodama i morfometrijskim analizama uz pomoć svetlosnog, elektronskog i konfokalnog mikroskopa... Warfarin (4-OH coumarin) is an anticoagulant of the first generation which is used as a drug and rodenticide. It’s main biological effect is achieved through inhibition of vitamin K-dependent path in a complete synthesis of many coagulation factors in the liver. Warfarin acts on proteins for which biological activity of vitamin K is necessary, such as proteins involved in the process of growth, bone calcification, proliferation of mesangial cells, and proteins involved in the transduction of cellular signals. By widespread use of warfarin as a drug and as a rodenticide, it’s numerous side effects have been noted. At therapeutic doses, it may cause acute and chronic side effects, such as skin necrosis and calcification of the arterial wall, and, besides anticoagulant, it can have proinflammatory and anti-inflammatory systemic effect. Improper handling in the production and use of warfarin as rodetnicide can lead to a single or repeated inhalational, oral or percutaneous exposure. Contact between skin and anticoagulant rodenticides can cause percutaneous intoxication with the development of coagulopathy and bleeding, death and local skin irritation. A particular problem presents unrecognized exposure to low doses of warfarin whose effects can be manifested as symptoms of an unknown disease and then warfarin can be seen as a xenobiotic. In our experimental study, we decided to examine the xenobiotic effects of warfarin in the skin, since it is a common route of exposure, and such effects of warfarin are not known. In initial studies we have found that epicutaneously applied warfarin show local and systemic proinflammatory, pro-oxidative and immunomodulatory effects and, depending on the applied dose, direct immunotoxic and dermatotoxic effect. Preliminary histomorphological analysis revealed changes in the skin that can, on the one hand, reflect the inflammatory-reparative program, but, on the other, can represent an introduction to the pathological events in the skin. In this study the effect of a single local epicutaneous application of warfarin on the skin of Dark Agouty rats at doses of 1μg, 10μg and 100μg was examined. The seven-day dynamics of selective functional parameters of oxidative stress, changes in the immune system, microvasculature, the cell cycle of keratinocytes and dermal fibroblasts and structural changes in the skin, have been analyzed by immunohistochemical methods and morphometric analysis with the help of light-, electron- and confocal microscope...