Phorbol-12,13-diester 12-ester hydrolase may prevent tumour promotion by phorbol diesters in skin

Abstract

Tumour promoters are not themselves carcinogenic but can induce tumours in mice treated previously with an otherwise insufficient dose of certain chemical carcinogens^1–6. One of the most potent tumour-promoting agents is 12-O-tetradecanoyl-phorbol-13-acetate (TPA), initially isolated from croton oil⁷. The effects of tumour promoters are species specific⁸; croton oil, of which TPA is the most active component, does not act as a tumour promoter in rat, rabbit, guinea pig or hamster skin in conditions for which it is a potent tumour promoter in mouse skin^8–12. Recently, we have purified the enzyme phorbol-12,13-diester 12-ester hydrolase (PDEH) to homogeneity from mouse and human liver cytosol¹³. This enzyme converts biologically active phorbol-12, 13-diesters to the inactive phorbol-13-monoester¹³ in a dose-, time- and temperature-dependent manner. PDEH has been partially purified from hamster skin but is not detected in mouse skin, suggesting that the basis for the TPA tumour promotion only in mouse skin is a result of differences between the species in levels of TPA inactivating enzyme (PDEH) in the skin. We demonstrate here that respon-siveness to TPA-induced tumour promotion is related to the level of PDEH activity in skin of all animals tested.