Toxicokinetics of tumor promoters of mouse skin. I. Metabolism of phorbol and ingenol esters by mouse liver microsomes.

ABSTRACT

The metabolism of ten selected phorbol esters and of one ingenol ester was investigated in mouse liver microsomes fortified with cofactors. The major metabolites were generated by an esterolytic activity in the microsomes. The following 12,13-diesters were cleaved readily to yield the 13-monoesters 12-O-tetradecanoylphorbol-13-acetate, phorbol-12,13-dipropionate, bis(13-O-acetylphorbol)-12, 12'-tetradecanedioate, phorbol-12,13-dibenzoate; the monoesters 12-O-tetradecanoylphorbol and 3-O-tetradecanoylingenol yielded the corresponding parent alcohols. Other 12,13-di- or 13-monoesters such as 'inverse TPA', i.e. 12-O-acetylphorbol-13-tetradecanoate, phorbol-12,13-didecanoate, 12-O-retinoylphorbol-13-acetate, phorbol-13-decanoate and 12-O-tetradecanoyl-4 alpha-phorbol-13-acetate were either comparatively or completely resistant to esterolysis. The data indicate that metabolism of diterpene esters depends on the nature and position of the acyl moiety, as well as on the structure of the diterpene moiety. The esterolytic activity in mouse liver microsomes can be inhibited by i.p. administration of bis(4-nitrophenyl)phosphate to mice. Evidence for other relevant metabolic pathways besides esterolysis was lacking.