In vivo inhibition of human CYP1A2 activity by oltipraz.
In vivo inhibition of human CYP1A2 activity by oltipraz.
复制标题
吡噻硫酮对人 CYP1A2 活性的体内抑制作用。
DOI：
10.1007/s002800000245
复制
发表时间：
2001
影响因子：
3
通讯作者：
Wilkinson,GR
中科院分区：
文献类型：
--
作者：
Sofowora,GG;Choo,EF;Mayo,G;Shyr,Y;Wilkinson,GR
目的：奥替普拉作为一种癌症化学预防剂，特别是在黄曲霉毒素相关的肝癌发生方面，目前正在进行临床评价。该药剂诱导II期异生素酶的能力，该酶可使体内形成的最终致癌物解毒，被认为是减轻疾病风险的重要机制。然而，另一种机制可能是某些细胞色素P450（P450）亚型对环境前致癌物的活化减少。这一假设进行了测试方面的CYP 1A 2，通过使用清除咖啡因的N-去甲基化作为一个表型性状测量的异构体的催化activity.Methods：受试者接受了一个单一的口服剂量的咖啡因（200毫克）在五个不同的场合：在奥替普拉给药前一天（第0天），奥替普拉（125 mg）每日8次口服给药的首次给药（第1天）后2 h和末次给药（第8天）后2 h。此外，还在奥替普拉停药后2天和14天（分别为第10天和第22天）测量了CYP 1A 2活性。血浆中咖啡因及其N-去甲基代谢产物副黄嘌呤的浓度，超过24小时后，药物administration.Results测定：一个单一的125毫克剂量的奥替普拉显着降低CYP 1A 2活性的75±13%，在9名健康受试者，导致较高的咖啡因血浆浓度和延长的体内探针的消除半衰期。每日给予125 mg奥替普拉，持续8天，导致进一步抑制，因此仅存在原始基线活性水平的19±13%。然而，2天后停止奥替普拉治疗，CYP 1A 2活性已恢复到66±33%的原始水平和完全恢复是在14天内实现的chemopreventive agents being stopped.Conclusions：这些结果表明，奥替普拉是一种有效的，在人体内的CYP 1A 2抑制剂，因为这种异构体是重要参与前致癌物的激活，他们也表明，这种抑制可能有助于奥替普拉的癌症chemopreventive效果。此外，研究结果还表明，奥替普拉与代谢由CYP 1A 2介导的药物之间可能存在显著的药物相互作用。
Purpose:Oltipraz is currently undergoing clinical evaluation as a cancer chemopreventive agent, especially with respect to aflatoxin-associated hepatocarcinogenesis. The agent's ability to induce phase II xenobiotic enzymes that detoxify the ultimate carcinogen formed in vivo is thought to be an important mechanism by which disease risk may be attenuated. However, an additional mechanism could be a reduction in the activation of environmental procarcinogens by certain cytochrome P450 (CYP) isoforms. This hypothesis was tested with respect to CYP1A2, by using the clearance of caffeine byN-demethylation as a phenotypic trait measurement of the isoform's catalytic activity.Methods:Subjects received a single oral dose of caffeine (200 mg) on five separate occasions: on the day prior to oltipraz administration (day 0), 2 h after the first (day 1) of eight daily oral doses of oltipraz (125 mg) and 2 h after the last dose (day 8). In addition, CYP1A2 activity was also measured 2 and 14 days (days 10 and 22, respectively) after discontinuation of oltipraz administration. Plasma concentrations of caffeine and itsN-demethylated metabolite, paraxanthine, over 24 h after drug administration, were determined by HPLC.Results:A single 125-mg dose of oltipraz markedly reduced CYP1A2 activity by 75±13% in nine healthy subjects, resulting in a higher caffeine plasma level and prolongation of the in vivo probe's elimination half-life. Daily administration of 125 mg oltipraz for 8 days resulted in further inhibition so that only 19±13% of the original baseline level of activity was present. However, 2 days after discontinuation of oltipraz treatment, CYP1A2 activity had returned to 66±33% of its original level and complete recovery was achieved within 14 days of the chemopreventive agent being stopped.Conclusions:These results demonstrate that oltipraz is a potent, in vivo inhibitor of CYP1A2 in humans and, because this isoform is importantly involved in procarcinogen activation, they also indicate that such inhibition probably contributes to oltipraz's cancer-chemopreventive effect. In addition, the findings also suggest the likelihood of significant drug interactions between oltipraz and drugs whose metabolism is mediated by CYP1A2.