Comparison of the effect of sn-1,2-didecanoylglycerol and 12-O-tetradecanoylphorbol-13-acetate on cutaneous morphology, inflammation and tumor promotion in CD-1 mice.
Since sn-1,2-didecanoylglycerol mimics 12-O-tetradecanoylphorbol-13-acetate (TPA) by inducing ornithine decarboxylase activity and stimulating DNA synthesis in mouse epidermis [Smart, R.C., Huang, M.-T. and Conney, A.H. Carcinogenesis, 7, 1865 (1986)], we have investigated morphological changes induced by TPA and sn-1,2-didecanoylglycerol in the epidermis and we have also examined sn-1,2-didecanoylglycerol as a possible complete tumor promoter. It was determined that topical application of 2.5 or 10 mumol of sn-1,2-didecanoylglycerol induced epidermal ornithine decarboxylase activity to about the same extent as the application of 1 or 2 nmol of TPA respectively. Therefore, these doses of TPA and sn-1,2-didecanoylglycerol were used in most of our studies. Single or multiple application (2 X/week for 4 weeks) of 1, 2 or 5 nmol of TPA to the skin of CD-1 mice produced a dose-dependent increase in the number of epidermal non-cornified cell layers, epidermal thickness, leukocyte infiltration and intracellular edema. In contrast, neither single nor multiple application (2 X/week for 4 weeks) of 2.5 or 10 mumol sn-1,2-didecanoylglycerol produced any of these responses. However, when 5 mumol sn-1,2-didecanoylglycerol was applied topically twice a day (10 mumol/day) for 5 days there was a significant increase in the number of epidermal non-cornified cell layers and epidermal thickness. The effects of TPA and sn-1,2-didecanoylglycerol were compared using the mouse ear inflammation model. Application of TPA caused edema, but sn-1,2-didecanoylglycerol had little or no effect. sn-1,2-Didecanoylglycerol was then evaluated as a complete tumor promoter utilizing the mouse skin two-stage model. CD-1 mice were initiated with 200 nmol 7,12-dimethylbenz[a]anthracene and then treated with 1 nmol TPA or 2.5 mumol sn-1,2-didecanoylglycerol twice a week for 28 weeks. A 28 weeks, 28% of the mice treated with TPA had developed tumors, while none of the mice treated with 2.5 mumol sn-1,2-didecanoylglycerol developed tumors. The data indicate that topical application of 2.5 mumol sn-1,2-didecanoylglycerol induced ornithine decarboxylase activity to the same extent as a tumor-promoting dose of 1 nmol TPA, but it did not cause morphological changes in the epidermis when applied once or when applied twice a week for 4 weeks and did not function as a complete tumor promoter when applied twice a week for 28 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)
Smart
R C
RC
Toxicology Program, North Carolina State University, Raleigh 27695-7633.
Huang
M T
MT
Monteiro-Riviere
N A
NA
Wong
C Q
CQ
Mills
K J
KJ
Conney
A H
AH
D000818:Animals; D002273:Carcinogens; D004075:Diglycerides / Q000633:toxicity*; D004487:Edema / Q000139:chemically induced; D004790:Enzyme Induction; D005260:Female; D005989:Glycerides / Q000633:toxicity*; D006965:Hyperplasia / Q000139:chemically induced; D051379:Mice; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D012867:Skin / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
D002273:Carcinogens; D004075:Diglycerides; D005989:Glycerides; C044297:1,2-didecanoylglycerol; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate