Effect of 12–O-Tetradecanoyl-Phorbol-13-Acetate and 3-Methylcholanthrene on the Toxicity of Nicotine Applied to Mouse Skin

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Abstract
The effect of the tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and 3-methylcholanthrene (MCA) on the toxicity of nicotine and the content of this alkaloid in mouse skin was determined following the application of these reagents to the skin. TPA or MCA was applied to mouse skin at time 0, and then at various time intervals thereafter, nicotine was applied to the skin. The content of this alkaloid (nicotine DNA ratio) remaining in the skin was then determined 1/2 h after its application. After the application of TPA, the nicotine DNA ratio of the skin decreased from 120 at 1.8 h to 80 at 18 h, increased sharply from 24 h, reaching a maximum of 165 at 72 h, and then decreased gradually. As the nicotine DNA ratio of the skin increased, the mortality rate of the mice also increased, reaching a maximum of over 40% at 48 and 72 h following the application of TPA. When MCA was applied to mouse skin in the same fashion and then nicotine, there was a decrease in the nicotine DNA ratio similar to that induced by TPA and nicotine followed by an average increase in the nicotine DNA ratio of 130 at 72, 96 and 120 h. The mortality rate of these mice was low. Ethyl phenyl propiolate (EPP) was applied to mouse skin at time 0, and nicotine was applied 24, 48, 72, 96 and 120 h later. The mortality rate was also quite low at these times 1/2 h after application of nicotine (nicotine was not determined in the skin). TPA has induced some change in the skin 24, 48, 72 and 96 h after its application which resulted in an increase in the toxicity of nicotine to mice. Nicotine was not detected by the gas chromatographic method employed in the serum or plasma of nicotine-treated, and TPA and nicotine-treated mice even though the mice showed acute reactions of nicotine toxicity and the skin surface contained ample amounts of this alkaloid.