Evaluation of the Developmental Toxicity of Theophylline, Dimethyluric Acid, and Methylxanthine Metabolites UsingXenopus

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Abstract
The developmental toxicities of theophylline and theophylline metabolites were evaluated using FETAX (Frog Embryo Teratogenesis Assay - Xenopus). Young X. laevis embryos were exposed to theophylline, 1-methylxanthine, 3-methylxanthine, or 1,3-dimethyluric acid in each of two separate concentration-response experiments with and without an exogenous metabolic activation system (MAS) and/or inhibited MAS. The MAS was treated with carbon monoxide (CO), cimetidine (CIM), or ellipticine (ELL) to selectively modulate cytochrome P-450 activity. Addition of the MAS and CIM-MAS reduced the developmental toxicity of theophylline. Addition of the ELL- or CO-inhibited MAS did not reduce the developmental toxicity of theophylline. Addition of the intact MAS did not alter the developmental toxicity of 1-methyl- or 3-methylxanthine which were slightly more developmentally toxic on an equimolar basis than theophylline itself. 1,3-dimethyluric acid was not developmentally toxic at maximum soluble concentrations in 1% (v/v) DMSO. Results from these studies suggested that P-450, specifically ELL-inhibited P-450 (aryl hydrocarbon hydroxylase) may have been responsible for detoxification of theophylline and that 1,3 dimethyluric acid represented the primary detoxification metabolite of theophylline.