Inhibition of specific binding of [3H]phorbol-12,13-dipropionate to an epidermal fraction by certain irritants and irritant promoters of mouse skin.
Specific binding of [3H]phorbol-12,13-dipropionate ([3H]PDPr) to a particulate fraction of mouse skin is demonstrated (KD = 35 nM; Rt = 1.2 pmol/mg protein). A series of compounds of the diterpene ester, indole akaloid and polyacetate types with different degrees of activity as skin tumor promoters and/or irritants have been tested for their capacity to inhibit specific [3H]PDPr binding. Three main categories are found: (i) compounds which exhibit a positive correlation between their potency as irritants and promoters in vivo and their inhibition of specific binding in vitro: 12-O-tetradecanoylphorbol-13-acetate, 3-O-tetradecanoylingenol, pimelea factor P2, 'teleocidin', dihydroteleocidin B, and lyngbyatoxin are active in vivo and in vitro, whereas phorbol and ingenol are inactive and 4-O-methyl-12-O-tetradecanoyl-phorbol-13-acetate is weakly active; (ii) compounds which are strong irritants and inhibitors of binding but are weak or practically non-promoters: mezerein, 12-O-retinoylphorbol-13-acetate and milliamine C; (iii) strong irritants which are weak or marginally active inhibitors of binding: debromoaplysiatoxin and resiniferatoxin. Some consequences of these findings with respect to interpretations of the biochemical mechanism(s) of tumor promotion are discussed.
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D007509:Irritants / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D010703:Phorbol Esters / Q000378:metabolism*; D010704:Phorbols / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism
D002273:Carcinogens; D007509:Irritants; D010703:Phorbol Esters; D010704:Phorbols; C033963:phorbol-12,13-dipropionate