ABILITY OF OKADAIC ACID AND OTHER PROTEIN PHOSPHATASE INHIBITORS TO MIMIC THE STIMULATORY EFFECTS OF 12-O-TETRADECANOYLPHORBOL-13-ACETATE ON HYDROPEROXIDE PRODUCTION IN MOUSE EPIDERMIS IN-VIVO

The non-12-O-tetadecanoylphorbol-13-acetate (TPA)-type tumor promoters , okadaic acid (OA) and calyculin-A (GAL-A), which neither interact wi th the phorbol ester receptor nor directly activate protein kinase C, mimic the stimulatory effects of and thapsigargin on hydroperoxide (HP x) production in mouse epidermis in vivo. The time course and dose dep endency for the stimulation of HPx production by O and TPA are similar . HPx production is maximally stimulated 16 h after two applications o f 2 nmol of OA at a 48-h interval. However GAL-A is a stimulator of HP x production about 4 times more potent than OA or TPA. Combinations of TPA and OA or GAL-A have subadditive effects on HPx production. The d iscrepancies between the abilities of various serine/threonine protein phosphatase (PP) inhibitors to stimulate HPx production suggest that PP inhibition alone is not sufficient for this response. Cycloheximide , Ca2+ antagonists, oxypurinol, diphenyliodonium, nordihydroguaiaretic acid, bromophenacyl bromide, antiinflammatory agents, and antihistami nes block or decrease OA-stimulated HPx production. Although most of t hese inhibitors may have more than one action, their effects suggest t hat protein synthesis, Ca2+, xanthine oxidase and NADPH oxidase activi ties, the lipoxygenase pathway of arachidonic acid metabolism, and vas cular permeability may be involved in the inflammatory and HPx respons es that occur after tumor promoter treatment. The increased HPx-produc ing activity of the epidermis, therefore, may be a common event result ing from the inflammatory and tumor-promoting actions of diverse TPA- and non-TPA-type agents.