Effect of iron overload on the benzoyl peroxide-mediated tumor promotion in mouse skin
Introduction
Benzoyl peroxide is a widely used free radical-generating compound with an estimated production of several million pounds per year. It is used in the polymer industry as a polymerization initiator, as a curing agent and as a cross-linking agent 1, 2. It is also used as an additive in cosmetics and pharmaceuticals, especially those related to the treatment of acne [3]. In skin-painting studies, BPO was shown to induce hyperplastic and morphological effects similar to those caused by 12-O-tetradecanoylphorbol-13-acetate (TPA) 4, 5. In further studies, BPO has also been shown to act as a weak tumor promoter in DMBA-initiated mouse skin. Similar to BPO, other organic peroxides and many hydroperoxides also act as tumor promoters and produce pathological responses as observed after TPA and BPO applications. Recently, we provided direct evidence for the involvement of reactive oxygen species (ROS) in skin tumor promotion. We showed that in situ generated ROS result in the development of cutaneous inflammation, epidermal hyperplasia, glandular hyperplasia and neutrophil infiltration, which are assumed to be some of the characteristic changes associated with stage I tumor promotion in murine skin [6]. In addition, in situ ROS acts as a weak tumor promoter [7]. It has been proposed that these peroxides and hydroperoxides, at least in part, act by generating free radicals [8]. It has also been shown that free radical generation by peroxides and hydroperoxides is catalyzed by iron [9]. It is also known that iron overload enhances lipid peroxide formation [10], suggesting that it may be catalyzing in situ degenerative reactions. Therefore, it is possible that BPO in iron-overloaded animals may be converted into free radicals leading to the enhancement of its tumor-promoting potential as compared to BPO per se. In this study, we therefore investigated the effect of iron overload on BPO-mediated cutaneous tumor promotion.
Section snippets
Chemicals
Iron dextran (imferon) was purchased from Rallis (India). Hair-removing cream was purchased from Anne French, Geoffrey Manners & Co. (India). Bovine serum albumin and BPO were from Aldrich (Milwaukee, WI). DMBA, brij 35, phenyl methylsulfonyl fluoride, pyridoxal 5-phosphate, 2-mercaptoethanol, dithiothreitol, thiobarbituric acid, hydrogen peroxide, Tween-80 and l-ornithine were procured from Sigma (St. Louis, MO). [14C]Ornithine (specific activity, 56 mCi/mmol) and [3H]thymidine (specific
Results
The effect of iron overload on the levels of iron in uninvolved skin, involved skin and tumor skin of DMBA-initiated and BPO-promoted animals is given in Fig. 1. Iron overload enhanced iron levels in skin by 2.5-fold. Tumor promotion by BPO slightly enhanced the level of iron in skin. However, there was no significant difference between BPO-promoted uninvolved skin and tumor-bearing skin. In iron-overloaded animals, a difference of about 4-fold was observed in iron levels between the skin
Discussion
BPO is a tumor promoter, produces a pleiotropic response in mouse skin and acts by the generation of free radicals. In addition, it produces many responses which are similar to phorbol ester-mediated tumor promotion in mouse skin [1]. BPO exposure results in the inhibition of metabolic cooperation between epidermal keratinocytes by inhibiting junctional communication 1, 18. It is also a primary human skin irritant and causes scaling and inflammation [19]. The mechanism of BPO tumor promotion
Acknowledgements
The authors are thankful to Professor A. Ahmad, Vice-chancellor, JH for providing necessary facilities. H.R. is thankful to Dr L. Mousavi, Department of Biology, Imam Hussain University, Tehran, Iran for his support and encouragement.
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