A simple phenolic antioxidant protocatechuic acid enhances tumor promotion and oxidative stress in female ICR mouse skin: Dose-and timing-dependent enhancement and involvement of bioactivation by tyrosinase

Yoshimasa Nakamura, Koji Torikai, Yoshimi Ohto, Akira Murakami, Takuji Tanaka, Hajime Ohigashi

Research output: Contribution to journalArticle

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Abstract

The modifying effects of topical application of the phenolic antioxidant protocatechuic acid (PA) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin tumor promotion were investigated. Dimethyl-benz[a]anthracene-initiated female ICR mice were treated with TPA (1.6 nmol) twice weekly for 20 weeks to promote papilloma formation. Pre-treatment with 16 nmol PA 30 min prior to each TPA treatment significantly inhibited the number of papillomas per mouse by 52% (P <0.05). On the other hand, PA pre-treatment at a high dose (1600 nmol) significantly enhanced tumor numbers by 38% (P <0.05). Interestingly, in the group treated with a quite high dose (20 000 nmol) of PA 5 min prior to each TPA application, the average number of tumors per mouse was reduced by 38%, whereas the same PA dose 3 h before TPA treatment significantly enhanced tumor numbers by 84% (P <0.01). These results suggested that topically applied PA was converted to compound(s) lacking antioxidative properties and/or rather possessing the potential to enhance tumor development. A similar tendency was also observed in the short-term experiment of TPA-induced inflammation and oxidative stress; i.e. two groups pretreated with PA at 20 000 nmol, 30 min and 3 h before TPA treatment, did not show suppression or even significantly enhanced TPA-induced leukocyte infiltration, H2O2 generation, thiobarbituric acid-reacting substances level and proliferating cell nuclear antigen index, while PA treatment together with TPA significantly suppressed these parameters. Treatment with a high dose (20 000 nmol) of PA alone for 3 h enhanced oxidative stress by reducing glutathione levels in mouse skin, which was counteracted by the tyrosinase inhibitor arbutin. Oxidative stress responses such as leukocyte infiltration and H2O2 generation were also counteracted by arbutin. These results suggested that tyrosinase-dependent oxidative metabolism of PA was at least partially involved in the enhanced effects of PA on TPA-induced inflammatory responses and thus tumor promotion.

Original languageEnglish
Pages (from-to)1899-1907
Number of pages9
JournalCarcinogenesis
Volume21
Issue number10
Publication statusPublished - 2000
Externally publishedYes

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Inbred ICR Mouse
Monophenol Monooxygenase
Tetradecanoylphorbol Acetate
Oxidative Stress
Antioxidants
Skin
Neoplasms
Arbutin
Papilloma
Leukocytes
protocatechuic acid
Proliferating Cell Nuclear Antigen
Glutathione

ASJC Scopus subject areas

  • Cancer Research

Cite this

A simple phenolic antioxidant protocatechuic acid enhances tumor promotion and oxidative stress in female ICR mouse skin : Dose-and timing-dependent enhancement and involvement of bioactivation by tyrosinase. / Nakamura, Yoshimasa; Torikai, Koji; Ohto, Yoshimi; Murakami, Akira; Tanaka, Takuji; Ohigashi, Hajime.

In: Carcinogenesis, Vol. 21, No. 10, 2000, p. 1899-1907.

Research output: Contribution to journalArticle

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abstract = "The modifying effects of topical application of the phenolic antioxidant protocatechuic acid (PA) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin tumor promotion were investigated. Dimethyl-benz[a]anthracene-initiated female ICR mice were treated with TPA (1.6 nmol) twice weekly for 20 weeks to promote papilloma formation. Pre-treatment with 16 nmol PA 30 min prior to each TPA treatment significantly inhibited the number of papillomas per mouse by 52{\%} (P <0.05). On the other hand, PA pre-treatment at a high dose (1600 nmol) significantly enhanced tumor numbers by 38{\%} (P <0.05). Interestingly, in the group treated with a quite high dose (20 000 nmol) of PA 5 min prior to each TPA application, the average number of tumors per mouse was reduced by 38{\%}, whereas the same PA dose 3 h before TPA treatment significantly enhanced tumor numbers by 84{\%} (P <0.01). These results suggested that topically applied PA was converted to compound(s) lacking antioxidative properties and/or rather possessing the potential to enhance tumor development. A similar tendency was also observed in the short-term experiment of TPA-induced inflammation and oxidative stress; i.e. two groups pretreated with PA at 20 000 nmol, 30 min and 3 h before TPA treatment, did not show suppression or even significantly enhanced TPA-induced leukocyte infiltration, H2O2 generation, thiobarbituric acid-reacting substances level and proliferating cell nuclear antigen index, while PA treatment together with TPA significantly suppressed these parameters. Treatment with a high dose (20 000 nmol) of PA alone for 3 h enhanced oxidative stress by reducing glutathione levels in mouse skin, which was counteracted by the tyrosinase inhibitor arbutin. Oxidative stress responses such as leukocyte infiltration and H2O2 generation were also counteracted by arbutin. These results suggested that tyrosinase-dependent oxidative metabolism of PA was at least partially involved in the enhanced effects of PA on TPA-induced inflammatory responses and thus tumor promotion.",
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T1 - A simple phenolic antioxidant protocatechuic acid enhances tumor promotion and oxidative stress in female ICR mouse skin

T2 - Dose-and timing-dependent enhancement and involvement of bioactivation by tyrosinase

AU - Nakamura, Yoshimasa

AU - Torikai, Koji

AU - Ohto, Yoshimi

AU - Murakami, Akira

AU - Tanaka, Takuji

AU - Ohigashi, Hajime

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