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

The expression pattern, enzymatic activity, and products of 8-lipoxygenase (LOX) were analyzed in normal and neoplastic skin of NMRI mice. While barel y detectable in normal epidermis, 8-LOX was transiently induced by 12-O-tet radecanoylphorbol-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 t he recombinant protein produced the S enantiomers of 8-hydroxy-5Z,9E,11Z,14 Z- eicosatetraenoic acid (8-HETE) and 9-hydroxy-10E,12Z- octadecadienoic ac id (9-HODE) as the main arachidonic acid- and linoleic acid-derived metabol ites. As compared with normal epidermis, papillomas exhibited 25- and 4-fol d elevated levels of 8-H ETE and 9-HODE, respectively. However, the varying S to R ratios of 8-HETE and the predominance of 9(R)-HODE indicated that i n addition to 8(S)-LOX, other enzymes yet to be defined may be involved in 8-HETE and 9-MODE production. The massive accumulation of both 8-HETE and 1 2-hydroxy-5Z, 8Z, 10E, 14Z-eicosatetraenoic acid (12-HETE) point to a criti cal role of these LOX pathways in epidermal tumor development, in particula r in the papilloma stage. Here we showed that 8- and 12-hydroperoxyeicosate traenoic acids and 8- and 12-HETE induce chromosomal alterations in cycling primary basal keratinocytes. Mol. Carcinog. 24: 108-117, 1999. (C) 1999 Wi ley-Liss. Inc.