Polycyclic Aromatic Hydrocarbon o-Quinones Inhibit the Activity of the Catalytic Fragment of Protein Kinase C†

Polycyclic aromatic hydrocarbons (PAHs) require metabolic activation to exert their carcinogenic effects. PAH trans-dihydrodiol proximate carcinogens are oxidized by aldo−keto reductases (AKRs) to their corresponding reactive and redox-active o-quinones which may have the properties of initiators and promoters. To determine whether these o-quinones target protein kinase C (PKC), their effects on human recombinant PKCα and PKCδ and the catalytic fragment of rat brain PKC were determined. Naphthalene-1,2-dione (NP-1,2-dione), benzo[a]pyrene-7,8-dione (BP-7,8-dione), and 7,12-dimethylbenz[a]anthracene-3,4-dione (DMBA-3,4-dione) potently inhibited (IC50 values 3−5 μM) the basal and stimulated activity of the holoenzymes PKCα and PKCδ in a dose-dependent manner. Inhibition of PKC by BP-7,8-dione was observed irrespective of whether PKCα activity was stimulated with phorbol 12-myristate 13-acetate (PMA), phosphatidylserine (PS), or Ca2+ or whether PKCδ was stimulated with phorbol 12-myristate 13-acetate (PMA) o...