Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Screening of Potential Anticancer Compounds from Marketed Drugs: Aripiprazole, Haloperidol, Miconazole, and Terfenadine Inhibit Cytochrome P450 2J2

시판 약물의 시토크롬 2J2 약물대사효소 저해능 탐색

  • Liu, Kwang-Hyeon (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University)
  • Received : 2011.08.25
  • Accepted : 2011.11.16
  • Published : 2011.11.30
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Abstract

Cytochrome P450 2J2 (CYP2J2) plays important roles in the metabolism of endogenous metabolites such as arachidonic acid as well as therapeutic drugs. CYP2J2 is overexpressed in human cancer tissues and cancer cell lines, as well as in epoxyeicosatrienoic acids (EETs) and CYP2J2-mediated metabolites, and prevent apoptosis of cancer cells. This study aimed to screen marketed drugs for inhibitory potential on CYP2J2 isoforms using human liver microsomes. The initial screen isolated 4 compounds, from 120 marketed drugs, that inhibited the CYP2J2-mediated astemizole O-demethylation more than 50% in the following the order: haloperidol (75%) > terfenadine (56%) > aripiprazole (55%) > miconazole (52%). Miconazole strongly inhibited CYP2J2-mediated ebastine hydroxylation ($IC_{50}$=11.2 ${\mu}M$) and terfenadine hydroxylation ($IC_{50}$=2.2 ${\mu}M$), and terfenadine also inhibited CYP2J2-mediated ebastine hydroxylation ($IC_{50}$=13.6 ${\mu}M$) in a dose dependent manner. The present data suggest that these drugs are potential candidates for further evaluation for their anti-cancer activities.

CYP2J2는 치료약물 및 아라키돈산과 같은 내인성 화합물의 대사에 중요한 역할을 수행하고 있는 효소이다. 최근, CYP2J2 단백질이 인체 종양 조직이나 종양 세포주에 과발현되어 있고, CYP2J2 효소의 작용에 의해 생성된 에폭시에이코사트리에논산(EETs)이 세포사멸을 방지한다는 것이 보고되었다. 본 연구는 시판중인 약물 120종을 대상으로 시토크롬 2J2 동종효소에 저해능을 가지는 화합물을 발굴하고자 하였다. 인체 간 마이크로솜 시료에 아스테미졸과 NADPH 재생성계 및 약물(50 ${\mu}M$)을 첨가한 후 15분간 반응시켜 생성된 대사물을 LC/MS/MS를 이용하여 분석하여 시토크롬 2J2 동종효소 활성의 변화를 평가하였다. 그 결과 할로페리돌, 터페나딘, 아리피프라졸, 미코나졸의 순으로 CYP2J2 효소 활성 저해능을 보였다. 미코나졸은 CYP2J2에 의해 매개되는 에바스틴($IC_{50}$=11.2 ${\mu}M$) 및 터페나딘($IC_{50}$=2.2 ${\mu}M$) 대사를 강력하게 저해하였다. 터페나딘 또한 CYP2J2 매개 에바스틴 대사를 농도 의존적으로 저해하였다($IC_{50}$=13.6 ${\mu}M$). 향후, 이들 약물을 대상으로 한 항암 활성 평가가 필요할 것으로 판단된다.

Keywords

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