Suppression by citrus auraptene of phorbol ester and endotoxin-induced inflammatory responses: role of attenuation of leukocyte activation

Auraptene (AUR), a citrus coumarin derivative, is one of the promising chem opreventive agents against skin, tongue, esophagus and colon carcinogenesis in rodents, We reported previously that AUR suppresses superoxide anion (O -2(-)) generation from inflammatory leukocytes in in vitro experiments, In the present study, we investigated the antiinflammatory activities of AUR u sing a 12-O-tetradecanoylphorbol-13-acetate-treated mouse skin model, and c ompared them with those nf umbelliferone (UMB), a structural analog of AUR that is virtually inactive toward O-2(-) generation inhibition. Double pre- treatments of mouse skin with AUR, but not UMB, markedly suppressed edema f ormation, hydrogen peroxide production, leukocyte infiltration, and the rat e of proliferating cell nuclear antigen-stained cells. These inhibitory eff ects by AUR are attributable to its selective blockade of the activation st age, as revealed by single pre-treatment experiments. In a murine macrophag e line, RAW 264.7, AUR significantly attenuated the lipopolysaccharide-indu ced protein expression of inducible isoforms of both nitric oxide synthase and cyclooxygenase, with decreased production of nitrite anion and prostagl andin E-2, and yet suppressed the release of tumor necrosis factor-alpha. C onversely, UMB did not show any inhibitory effect, This contrasting activit y profile between AUR and UMB was rationalized to be a result of their dist inct differences in cellular uptake efficiencies, i.e. the geranyloxyl grou p in AUR was found to play an essential role in incorporation Thus, our fin dings indicate that AUR is an effective agent to attenuate the biochemical responsiveness of inflammatory leukocytes, which may be essential for a gre ater understanding of the action mechanism that underlies its inhibition of inflammation-associated carcinogenesis.