Tumour promoter phorbol-12-myristate-13-acetate induces chromosomal damage via indirect action

The mouse skin tumour promoter phorbol-12-myristate-13-acetate (PMA) does not form covalent adducts with cellular DNA and its mutagenic potency in several systems is low or absent 1–6 . There have been conflicting reports of the capacity of PMA to produce sister chromatid exchanges (SCEs) 3,6–8 . As PMA induces the formation of superoxide radicals in polymorphonuclear leukocytes and mitogen-stimulated lymphocytes 9–11 , we suggested that it might produce DNA damage via indirect action by the formation of intermediate active oxygen species 12,13 . As is typical for other DNA-damaging agents which mainly act indirectly, for example, ionizing radiation, PMA would be expected to have low mutagenicity but high clastogenic (chromosome-breaking) activity 14 . In agreement with this, we report here that PMA, but not its weakly or non-promoting derivatives, induced chromosomal aberrations with high efficiency in phytohaemagglutinin (PHA)-stimulated human lymphocytes, but was only a weak producer of SCE. This activity was suppressed by superoxide dismutase, which catalyses the breakdown of superoxide radicals.