In vivo inhibition of human CYP1A2 activity by oltipraz

Gbemiga G. Sofowora, Edna F. Choo, Gail Mayo, Yu Shyr, Grant R. Wilkinson

研究成果: Article同行評審

36 引文 斯高帕斯(Scopus)

摘要

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 by N-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 its N-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.

原文English
頁(從 - 到)505-510
頁數6
期刊Cancer Chemotherapy and Pharmacology
47
發行號6
DOIs
出版狀態Published - 2001

All Science Journal Classification (ASJC) codes

  • 腫瘤科
  • 毒理學
  • 藥理
  • 癌症研究
  • 藥學(醫學)

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