Oxidant Generation in Mouse Skin in Response to Phorbol Ester Tumor Promoters

Abstract

Oxygen radicals are believed to play an important role in cellular pathologies such as reperfusion injury, xenobiotic-induced toxicity, and chemically-induced cancer. Strong circumstantial evidence suggests generation of oxygen radicals is a key component of tumor promotion in multiple stage mouse skin tumorigenesis (1–4). However, there are few reports that demonstrate production of oxidants in mouse skin in vivo following administration of tumor promoters (5). The principal reason for the paucity of information on this key experimental point is the short lifetime of oxidizing radicals (typically ms-ms) (6). The ephemeral character of oxygen radicals necessitates indirect approaches to their detection. This frequently involves the use of freshly isolated epidermal cells or homogenates as models for intact epidermis. For example, the potent tumor promoter tetradecanoyl phorbol acetate (TPA) enhances oxidant production in isolated murine keratinocytes and neutrophils (7–11), stimulates the production of hydrogen peroxide ex vivo in cells isolated from TPA-treated mice (12), and stimulates lipid hydroperoxide production ex vivo mouse by epidermal homogenates prepared from TPA-treated mice (13).