Phytol Is a Novel Tumor Promoter on ICR Mouse Skin

Abstract

Phytol is a branched, long-chain aliphatic alcohol which has various biological effects. In this study, we examined phytol as a tumor promoter in a mouse skin initiation-promotion model, and compared its promotion activity with that of 12-O-tetradecanoyl phorbol-13-acetate (TPA). Female ICR mice, 7 weeks of age, were initiated with 100 µ µ µ µg of 7,12-dimethylbenz(a)anthracene, and were then topically promoted twice a week for 16 weeks with 100 mg of phytol or with 2.5 µ µ µ µg of TPA.In this model 95% of animals treated with phytol developed skin tumors within 16 weeks. The average number of lesions per mouse treated with phytol was significantly lower than that in mice treated with TPA, and this significant difference continued up to 16 weeks after the end of promotion treatment. Characterization of hyperplasia 48 h after topical application of agents showed that epidermal thickness and vertical thickness following topical application of phytol were significantly increased compared with vehicle controls, but were significantly smaller than in animals treated with TPA. Ornithine decarboxylase (ODC) activity following topical application of phytol was increased in a dose-dependent manner and showed a weak, delayed induction (which was maximal 11-12 h after treatment) as compared with the case of TPA. The specific binding of [ 3 H]phorbol-12,13-dibutyrate (PDBU) by JB6 cells was not inhibited by phytol at concentrations up to 1 mM. These results indicate that phytol has a weak tumor promoter activity compared to TPA and is a non-TPA-type tumor promoter in this model of mouse skin carcinogenesis. Key words:Phytol -Non-TPA-type tumor promoter -Two-stage mouse skin carcinogenesisOrnithine decarboxylase -Radioligand assay Mouse skin tumorigenesis can be divided into distinct stages of tumor initiation and promotion. According to carcinogenesis experiments, tumor development on mouse skin can be provoked by topical application of an initiator, such as the polycyclic aromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA), followed by repeated treatment with a tumor promoter.1, 2) Our current understanding of responses to skin tumor promoters has been derived primarily from studies with 12-O-tetradecanoylphorbol-13-acetate (TPA), which affects basal cells but not differentiating cells in mouse epidermis.3) While TPA is the strongest and most widely studied skin tumor promoter, other chemical compounds are known to possess tumorpromoting properties in mouse skin. There have been many reports which have described TPA-type promoters, such as Roussin red methyl ester, 4) and teleocidin, 5) and non-TPA-type promoters, such as okadaic acid, 6) thapsigargin, 7,8) and mirex. 9)Phytol (3,7,11,15-tetramethyl-2-hexadecen-1-ol), the fatty acid side chain of tocopherol, is a branched, longchain aliphatic alcohol contained in large quantities in plants and is a component of chlorophyll. In recent extensive studies, various cellular and biological effects of phytol have been demonstrated, such as its action as an agonist in hypox...

Immunohistochemical localization of ornithine decarboxylase in skin tumors

“…The biochemical method used to detect ODC activity is based on the release of 14 CO 2 from [ 14 C-ornithine] hydrochloride. 3,19 That assay has the advantage of detecting ODC induction at early time points following TPA treatment, 20 however it only provides information as to the average amount of 14 CO 2 formed by extracts obtained from tissue samples. Therefore, the assay does not allow detection of levels of ODC within subpopulations of cells which may have different amounts of ODC activity.…”

Immunohistochemical study of inducible nitric oxide synthase in skin cancers

“…Ornithine decarboxylase (ODC) is the first, and the rate‐limiting enzyme in the biosynthesis of polyamines. Induction of ODC and polyamine synthesis is found in regenerating tissue 28 and moreover, we previously demonstrated an induction of ODC in experimental and non‐experimental skin neoplasms 29,30 . These findings suggest that ODC plays an important role in cell proliferation and differentiation.…”

Medicinal and pesticidal potentials of the constituents of the essential oil from Adenia cissampeloides leaves

“…Phytol has also been reported to be a tumour promoter on l CR mouse skin. 123 Phytol and derivatives are the subject of a patent claiming that these compounds can serve as active ingredients in medicaments to lower serum levels of triglycerides and/or cholesterol, and can be administered to patients with disease conditions, such as type II diabetes, obesity or patients with cardiovascular disease. 124 These findings may also explain the anti-hypertensive activity of A. cissampeloides, and suggest the usefulness of the plant in the management of type II diabetes and obesity.…”