Fort D J, Stover E L, Propst T, Hull M A, Bantle J A
Stover Group, Stillwater, OK, USA.
Drug Chem Toxicol. 1996 Nov;19(4):267-78. doi: 10.3109/01480549608998237.
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.
使用FETAX（非洲爪蟾胚胎致畸试验）评估了茶碱及其代谢产物的发育毒性。在两个单独的浓度反应实验中，将非洲爪蟾幼胚暴露于茶碱、1-甲基黄嘌呤、3-甲基黄嘌呤或1,3-二甲基尿酸中，实验设置了有无外源性代谢激活系统（MAS）和/或抑制的MAS。用一氧化碳（CO）、西咪替丁（CIM）或玫瑰树碱（ELL）处理MAS以选择性调节细胞色素P-450活性。添加MAS和CIM-MAS降低了茶碱的发育毒性。添加ELL或CO抑制的MAS并没有降低茶碱的发育毒性。添加完整的MAS并没有改变1-甲基或3-甲基黄嘌呤的发育毒性，在等摩尔基础上，它们的发育毒性比茶碱本身略高。在1%（V/V）二甲基亚砜中的最大可溶浓度下，1,3-二甲基尿酸没有发育毒性。这些研究结果表明，细胞色素P-450，特别是ELL抑制的细胞色素P-450（芳烃羟化酶）可能参与了茶碱的解毒过程，并且1,3-二甲基尿酸是茶碱的主要解毒代谢产物。
