Studies on the tumor‐promoting activity of additives in biomaterials: Inhibition of metabolic cooperation by phenolic antioxidants involved in rubber materials

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Abstract
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 μg/ml were noted. These concentrations were close to the lowest effective inhibitory concentration (1.3 μg/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. © 1995 John Wiley & Sons, Inc.