Document Detail


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.
MedLine Citation:
PMID:  11023549     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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. Dimethylbenz[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 16nmol 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 (20000 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 pre-treated with PA at 20000 nmol, 30min and 3h before TPA treatment, did not show suppression or even significantly enhanced TPA-induced leukocyte infiltration, H(2)O(2) 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 (20000 nmol) of PA alone for 3h 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 H(2)O(2) 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.
Authors:
Y Nakamura; K Torikai; Y Ohto; A Murakami; T Tanaka; H Ohigashi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Carcinogenesis     Volume:  21     ISSN:  0143-3334     ISO Abbreviation:  Carcinogenesis     Publication Date:  2000 Oct 
Date Detail:
Created Date:  2000-11-01     Completed Date:  2000-11-03     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1899-907     Citation Subset:  IM    
Affiliation:
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
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MeSH Terms
Descriptor/Qualifier:
9,10-Dimethyl-1,2-benzanthracene / antagonists & inhibitors,  toxicity
Animals
Antioxidants / pharmacokinetics,  pharmacology*,  toxicity
Biotransformation
Carcinogens / antagonists & inhibitors,  pharmacology*,  toxicity
Dermatitis, Contact / metabolism
Dose-Response Relationship, Drug
Drug Administration Schedule
Drug Synergism
Female
Glutathione / metabolism
Glutathione Peroxidase / metabolism
Glutathione Transferase / metabolism
Hydrogen Peroxide / metabolism
Hydroxybenzoic Acids / pharmacokinetics,  pharmacology*,  toxicity
Mice
Mice, Inbred ICR
Monophenol Monooxygenase / metabolism*
Oxidative Stress / drug effects*
Papilloma / chemically induced*,  metabolism,  prevention & control
Skin / drug effects,  metabolism,  pathology
Skin Neoplasms / chemically induced*,  metabolism,  prevention & control
Tetradecanoylphorbol Acetate / antagonists & inhibitors,  toxicity
Chemical
Reg. No./Substance:
0/Antioxidants; 0/Carcinogens; 0/Hydroxybenzoic Acids; 16561-29-8/Tetradecanoylphorbol Acetate; 57-97-6/9,10-Dimethyl-1,2-benzanthracene; 70-18-8/Glutathione; 7722-84-1/Hydrogen Peroxide; 99-50-3/protocatechuic acid; EC 1.11.1.9/Glutathione Peroxidase; EC 1.14.18.1/Monophenol Monooxygenase; EC 2.5.1.18/Glutathione Transferase

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