Effects of capsaicin on chemically-induced two-stage mouse skin carcinogenesis

CANCER LETTERS

ELSEVIER

Cancer

Letters 114

(1997)

183-184

Effects of capsaicin on chemically-induced two-stage mouse skin carcinogenesis Kwang-Kyun Parka, Young-Joon Surhby* “College of Dentistry, Yonsei University, Seoul 120-752, South Korea bCollege of Pharmacy, Seoul National University, Seoul 151-742, South Korea

Abstract

Capsaicin@runs-8-methyl-N-vanillyl-6-nonenamide) is a principalpungentingredientof hot red peppers.Thereare some controversieswith regardto its inherenttumorigenicityandmutagenicity.The presentwork wasundertakento assess tumor initiating andpromotionaleffectsof capsaicinin a two-stagemouseskincarcinogenesis model.A singletopicalapplicationof caps&in (10 pmol) followed by twice-weeklyapplicationsof 12-0-tetradecanoylphorbol-13-acetate onto shavenbacksof femaleICR miceresultedin no significantincreases in incidenceandmultiplicity of skintumors,comparedwith the solventpretreatedcontrol animals.Repeatedtopical applicationsof capsaicinalonefailed to promote7,12-dimethylbenz[a]anthracene-initiatedmouseskintumorigenesis, but moderatelyinhibitedthe papillomaformationwhengiven prior to eachtopical doseof phorbolester. 0 1997ElsevierScienceIrelandLtd. Keywords: Capsaicin;Tumor promotion;Carcinogenesis

1. Introduction Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide; structure shown in Fig. l), a major pungent principle of hot chili peppers, has been extensively investigated for its effects on experimental carcinogenesisand mutagenesis,but results are discordant. While some studies revealed the tumor-initiating potential of capsaicin, others suggestedthat the compound might act as a co-carcinogen or a tumor promoter [ 1,2]. In an attempt to elucidate its tumorinitiating activity, capsaicin(10 pmol) in 0.2 ml acetone wastopically applied onto shavenbacks of female ICR mice (about 6 weeks of age) followed by twice-

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weekly treatment with the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) for 22 weeks. There were no appreciable increases in incidence and multiplicity of skin papillomas in capsaicin-treated mice as comparedwith thoseobservedin acetonetreated controls. Capsaicinwas also testedfor its possible tumor-promotional activity in the two-stage mouseskin carcinogenesisafter initiation with 7,12dimethylbenz[a]anthracene (DMBA). Repeatedtopical applications (twice weekly for 22 weeks) of 10 pmol of capsaicin following initiation dose (0.2 Fmol) of DMBA resulted in no significant enhancement of skin tumor formation in ICR mice compared with animalstreated with DMBA alone (Table 1). In another experiment, capsaicintreatment 30 min prior to each topical application of TPA lowered the incidence of DMBA-initiated mouse skin tumorigenesis by 22% at the 15th week while the multiplicity was

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Table

1

Lack of the tumor promotional mouse skin tumorigenesis Initiator

DMBA DMBA DMBA

Promoter

Capsaicin -Capsaicin TP.4

activity

of capsaicm

in two-stage -

At the 22nd week o/c tumor-bearing mice

Average no. 01 papillomas/mouse

0 0 8 3 100

(1 0 0.08 i. 0.28 0.04 i 0.20 9.24 i 5.2 I

Groups of 30 young adult female ICR mice were treated with a single topical dose of DMBA (0.2 pmol) in 0.2 ml acetone or the solvent alone. One week after the initiation, 10 amol of capsaicin or 15 nmol of TPA was applied onto the shaven backs of the mice twice weekly until termination of the experiment. Control animals were pretreated with the acetone in lieu of tire carcinogen followed by topical applications of capsaicin or the acetone alone.

not much affected (8.5 + 7.3 without capsaicin vs. 7.1 f 8.1 with capsaicin). We have recently reported that capsaicin inhibits rat hepatic cytochrome P450 2El activity, and suppresses the S9-mediated mutagenicity of vinyl carbamate (VC) and N-nitrosodimethylamine that are known to be preferentially activated by this isoform [3]. Pretreatment of female ICR mice with a single topical dose of capsaicin (10 pmol) resulted in diminution of VC-induced tumorigenesis in the skin as demonstrated by reduction of tumor multiplicity by 30%. In contrast, capsaicin enhanced skin tumor-initiating activity of vinyl carbamate epoxide (VCO), which is the ultimate electrophilic and carcinogenic metabolite of VC. The latter effects appears to be associated with possible inhibitory effects of capsaitin on epoxide hydrolase or glutathione S-transferase

Fig. I. Chemical

structure

of capsaicin.

activity responsible for detoxification of VCO. Further studies should follow to determine whether capsaicin can affect the mouse epidermal xenobiotic metabolizing activities, including cyt P450 2E1, glutathione S-transferase, and epoxide hydrolase.

Acknowiedgements This work was financially supported by the Korea Science and Engineering Foundation (KOSEF Grants 1994 and 1995). RePerences Surh, Y.-J. and Lee, S.S. (1995) Capsaicin, a double-edged sword: toxicity. metabolism, and chemopreventive potential, Life Sci., 56, 1845-1855. Stub, Y.-J. and Lee, S.S. (1996) Capsaicin in hot chili pepper: carcinogen, co-carcinogen or anticarcinogen?, Food Chem. Toxicol., 34, 313-316. Surh, Y.-J., Lee, R.C.-J., Park, K.-K., Mayne. S.T., Liem. A. and Miller. J.A. (1995) Chemoprotective effects of capsaicin and diallyl sulfide against mutagenesis or tumorigenesis by vinyl carbamate and ii-nitrosodimethylamine, Carcinogenesis, 16. 2461-247 1.