GINGIVAL OVERGROWTH: ROLE OF PHENYTOIN METABOLITES

据估计，美国有400万至500万癫痫患者 用5，5-二苯基海因(PHT，苯妥英)治疗。这一点 人口，约200万至300万人(“响应者”) 由于药物的不良影响，导致牙龈过度生长。研究 在人类和模型杂种猫群体中，已经表明PHT 代谢物可能通过选择 对于合成的高度活跃的牙龈成纤维细胞亚群， 它们会在易感人群中扩散。一群儿科医生 接受PHT治疗的患者将被分为有效或无效两类 以口试为基础的个人考试。尿液中的代谢产物 这些个体将通过气相色谱和 高压液相色谱(HPLC法)测定药物的状态 共轭、立体化学组成和酚类化合物的相对含量 (对HPPH，5-(4-羟基苯基)-5-苯基海因)和二氢二醇(DHD，5-(3， 4-二羟基-1，5-环己二烯-1-基)-5-苯基海因)，以及其他次要的 苯丙氨酸的代谢物。这些数据将被用来确定新陈代谢 人类应答者和非应答者群体之间存在差异。 应答者、无应答者和p-HPPH和p-HPPH和 DHD以确定这些化合物可能具有的细胞毒性或促有丝分裂作用 拥有。牙周成纤维细胞体外代谢PHT的方式 培养物将通过高效液相色谱技术进行检测和比较。这个 应答者和无应答者尿p-HPPH和DHD的立体化学 混血猫将被拿来比较。外消旋p-Hpph的能力及其作用 对映体诱导有反应的杂种猫牙龈过度生长 也要接受评估。这样的研究将允许评估潜在的毒性 应答者和非应答者的氧化芳烃和其他代谢途径 个体，这些代谢产物的生物活性，以及 活性代谢物的产生部位(肝脏和/或牙龈)。 通过对诱导的生物化学机制的补充洞察 牙龈过度生长，有可能开发出筛查程序来 识别潜在的易感人群。设计的新理论 毒性较低的抗癫痫药也可能被开发出来。

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.