GINGIVAL OVERGROWTH: ROLE OF PHENYTOIN METABOLITES

牙龈过度生长：苯妥英代谢物的作用

• 批准号: 3220069
• 负责人: JAMES H MAGUIRE
• 金额: $ 9.19万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1986-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3220069
• 关键词: anticonvulsants; child (0-11); drug adverse effect; drug metabolism; fibroblasts; gingiva hyperplasia; human subject; phenytoin; stereochemistry; tissue /cell culture; urinalysis

It is estimated that four to five million epileptics in he United States are treated with 5, 5-diphenylhydantoin (PHT, phenytoin). Of this population, approximately two to three million individuals ("responders") develop gingival overgrowth as an undesirable effect of the drug. Studies in human and model mongrel cat populations have suggested that PHT metabolites may be responsible for development of the lesion by selecting for a subpopulation of synthetically hyperactive gingival fibroblasts, which proliferate in susceptible individuals. A population of pediatric patients on PHT therapy will be classified as responder or non-responder individuals on the basis of oral examinations. Urinary metabolites from such individuals will be quantitated by gas chromatography and high-pressure liquid chromatography (HPLC) to determine the state of conjugation, stereochemical composition, and relative amounts of phenolic (p-HPPH, 5-(4-hydroxyphenyl)-5phenylhydantoin) and dihydrodiol (DHD, 5-(3, 4-dihydroxy-1, 5-cyclohexadien-1-yl)-5-phenylhydantoin), and other minor metabolites of PHT. These data will be used to determine if metabolic differences exist between the human responder and non-responder groups. Gingival fibroblast cultures from responder, non-responder, and p-HPPH and DHD to determine what cytotoxic or mitogenic effects such compounds may possess. The mode of PHT metabolism by in vitro gingival firbroblast cultures will be examined and compared by use of HPLC techniques. The stereochemistry of urinary p-HPPH and DHD in responder and non-responder mongrel cats will be compared. The ability of racemic p-Hpph and its enantiomers to induce gingival overgrowth in responder mongrel cats will also be evaluated. Such studies will allow evaluation of potentially toxic arene oxide and other metabolic pathways in responder and non responder individuals, the biological activity of such metabolic products, and the sites (liver and/or gingivae) of production of the active metabolites. With the added insights into the biochemical mechanism of the induction of gingival overgrowth, it may be possible to develop screening procedures to identify potentially susceptible individuals. New theories for the design of less-toxic antepileptic drugs may also be developed.

据估计，美国的四到五百万癫痫 用5个5-二苯基氢化剂（PHT，苯妥英钠）处理。 这 人口，大约2至300万个人（“响应者”） 发展牙龈过度生长是该药物的不良作用。 研究 在人类和模型的杂种猫种群中，PHT 代谢物可能通过选择 对于合成多动态牙龈成纤维细胞的亚群， 在易感人群中扩散。 小儿种群 PHT治疗的患者将被归类为响应者或无响应者 根据口腔检查的个人。 来自 这样的个体将通过气相色谱法和 高压液相色谱（HPLC）以确定状态 共轭，立体化学组成和酚类相对量 （p-hpph，5-（4-羟基苯基）-5苯基氢二醇（DHD，5-（3，3，） 4-二羟基-1，5-胞糖exadien-1-基）-5-苯基氢化）和其他次要的 PHT的代谢产物。 这些数据将用于确定是否代谢 人类响应者和无响应组之间存在差异。 来自响应者，无响应者和P-HPPH的牙龈成纤维细胞培养物以及 DHD确定这些化合物的细胞毒性或有丝分裂作用 具有。 通过体外牙龈firbrobros的代谢模式 将通过使用HPLC技术来检查和比较培养物。 这 尿液P-HPPH和DHD的立体化学在响应者和无反应器中 将比较杂种猫。 消极的p-hpph及其能力 对映异构体诱导牙龈过度生长的响应者猫猫会 也可以评估。 这样的研究将允许评估潜在的有毒 响应者和非响应者中的氧化物和其他代谢途径 个体，这种代谢产物的生物学活性以及 活性代谢产生的位点（肝脏和/或牙龈）。 随着对诱导的生化机制的增加的见解 牙龈过度生长，可能有可能制定筛选程序 确定潜在的易感人物。 设计的新理论 还可以开发出较少的毒性肠药。