13-(S)-Hydroxyoctadecadienoic acid (13-HODE), the lipoxygenase metabolite of linoleic acid, has been shown to reverse the epidermal hyperproliferation induced by topical application of docosahexaenoic acid (DNA, 22:6 n-3) on guinea pig skin. Our initial studies demonstrated that 13-HODE exerts a selective inhibition of the membrane-bound PKC-beta activity in the hyperproliferative skin. To delineate the antiproliferative effects of 13-HODE, we investigated the nuclear events associated with this process. Our data demonstrated that the major PKC isozymes in the epidermal nuclear fraction are alpha and zeta. Epidermal hyperproliferation induced by DHA caused an increase in nuclear total PKC and atypical PKC activities, and this was accompanied by an increase in the two nuclear isozymes, alpha and zeta (P < 0.05). This increase was reversed after topical application of 13-HODE. Similarly, 13-HODE suppressed elevated nuclear MAP-kinase. Taken together, these data suggest that nuclear signalling events in the epidermis involve PKC-MAP-kinase pathway.