Constitutive expression of 8-lipoxygenase in papillomas and clastogenic effects of lipoxygenase-derived arachidonic acid metabolites in keratinocytes

Abstract

The expression pattern, enzymatic activity, and products of 8‐lipoxygenase (LOX) were analyzed in normal and neoplastic skin of NMRI mice. While barely detectable in normal epidermis, 8‐LOX was transiently induced by 12‐O‐tetradecanoylphorbol‐13‐acetate and constitutively expressed in papillomas but not carcinomas obtained by the initiation‐promotion protocol of mouse skin carcinogenesis. The product profile and chirality of both the native and the recombinant protein produced the S enantiomers of 8‐hydroxy‐5Z,9E,11Z,14Z‐eicosatetraenoic acid (8‐HETE) and 9‐hydroxy‐10E,12Z‐octadecadienoic acid (9‐HODE) as the main arachidonic acid– and linoleic acid–derived metabolites. As compared with normal epidermis, papillomas exhibited 25‐ and 4‐fold elevated levels of 8‐HETE and 9‐HODE, respectively. However, the varying S to R ratios of 8‐HETE and the predominance of 9(R)‐HODE indicated that in addition to 8(S)‐LOX, other enzymes yet to be defined may be involved in 8‐HETE and 9‐HODE production. The massive accumulation of both 8‐HETE and 12‐hydroxy‐5Z,8Z,10E,14Z‐eicosatetraenoic acid (12‐HETE) point to a critical role of these LOX pathways in epidermal tumor development, in particular in the papilloma stage. Here we showed that 8‐ and 12‐hydroperoxyeicosatetraenoic acids and 8‐ and 12‐HETE induce chromosomal alterations in cycling primary basal keratinocytes. Mol. Carcinog. 24:108–117, 1999.