Müller G, Hergenhahn M, Roeser H, Tremp G L, Schmidt R, Hecker E
Institute of Biochemistry, German Cancer Research Center, Heidelberg.
Carcinogenesis. 1990 Jul;11(7):1127-32. doi: 10.1093/carcin/11.7.1127.
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.
在添加了辅因子的小鼠肝脏微粒体中，研究了十种选定的佛波酯和一种大戟醇酯的代谢情况。主要代谢产物是由微粒体中的酯解活性产生的。以下12,13 - 二酯很容易被裂解生成13 - 单酯：12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯、佛波醇 - 12,13 - 二丙酸酯、双（13 - O - 乙酰佛波醇） - 12,12'- 十四烷二酸酯、佛波醇 - 12,13 - 二苯甲酸酯；单酯12 - O - 十四烷酰佛波醇和3 - O - 十四烷酰大戟醇生成了相应的母体醇。其他12,13 - 二酯或13 - 单酯，如“反向TPA”，即12 - O - 乙酰佛波醇 - 13 - 十四烷酸酯、佛波醇 - 12,13 - 二十二酸酯、12 - O - 视黄酰佛波醇 - 13 - 乙酸酯、佛波醇 - 13 - 癸酸酯和12 - O - 十四烷酰 - 4α - 佛波醇 - 13 - 乙酸酯，要么相对抗酯解，要么完全抗酯解。数据表明，二萜酯的代谢取决于酰基部分的性质和位置，以及二萜部分的结构。通过给小鼠腹腔注射双（4 - 硝基苯基）磷酸酯，可以抑制小鼠肝脏微粒体中的酯解活性。除酯解外，缺乏其他相关代谢途径的证据。
