Studies on the tumor-promoting activity of additives in biomaterials: inhibition of metabolic cooperation by phenolic antioxidants involved in rubber materials.
For the detection of tumor-promoting activities of phenolic antioxidants, the inhibitory activities on the intercellular gap-junctional communication were investigated using the V79 metabolic cooperation (MC) assay. Among eight antioxidants, 4,4'-butylidene-bis(3-methyl-6-tert-butyl-phenol), 2,2'-methylene-bis(4-methyl-6-tert-butylphenol) (MBMBP), and styrenated phenol (SP) showed stronger inhibitory activities than lithocholic acid, which is known to be a tumor promotor. However, 4,4'-thio-bis(3-methyl-6-tert-butylphenol), Irganox 1010, and 1330 did not inhibit at any concentrations. When the single-electron oxidation potentials were compared among antioxidants, the electrochemical ease estimated with the first oxidation potential was correlated with the cytotoxic potentials (r = 0.88), but not with the inhibitory activities in an MC assay. The tumor-promoting activity of MBMBP was also investigated using an in vitro, two-stage Balb/c 3T3 transformation assay. MBMBP did not show initiating activity, but significant promoting activity at concentrations of both 1 and 2.5 micrograms/ml were noted. These concentrations were close to the lowest effective inhibitory concentration (1.3 micrograms/ml) of MBMBP in an MC assay. In conclusion, there is a possibility that the phenolic antioxidants that show inhibitory activities in an MC assay contribute to the enhancement of tumor incidence induced by biomaterials.
Tsuchiya
T
T
Division of Medical Devices, National Institute of Health Sciences, Tokyo, Japan.
Fukuhara
K
K
Hata
H
H
Ikarashi
Y
Y
Miyata
N
N
Katoh
F
F
Yamasaki
H
H
Nakamura
A
A
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D002450:Cell Communication / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D004563:Electrochemistry; D017629:Gap Junctions / Q000187:drug effects; D051379:Mice; D010084:Oxidation-Reduction; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D012408:Rubber / Q000737:chemistry*
D000975:Antioxidants; D001672:Biocompatible Materials; D002273:Carcinogens; D010636:Phenols; D012408:Rubber