Evaluation of the developmental toxicity of theophylline, dimethyluric acid, and methylxanthine metabolites using Xenopus.
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.
Fort
D J
DJ
Stover Group, Stillwater, OK, USA.
Stover
E L
EL
Propst
T
T
Hull
M A
MA
Bantle
J A
JA
D000014:Abnormalities, Drug-Induced; D000818:Animals; D004625:Embryo, Nonmammalian / Q000187:drug effects*; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D013806:Theophylline / Q000378:metabolism / Q000633:toxicity*; D014527:Uric Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D014970:Xanthines / Q000633:toxicity*; D014982:Xenopus laevis / Q000196:embryology*
D014970:Xanthines; D014527:Uric Acid; C008514:methylxanthine; D013806:Theophylline; C031274:1,3-dimethyluric acid