东南亚地区疟原虫开始对青蒿素类抗疟药（QHS）产生耐药，环期延长很可能是重要原因；关于QHS的代谢研究多集中在中间宿主，而疟原虫对该类药物的代谢缺乏报道，其对中间宿主代谢的调控机制也不清楚。我们前期发现，QHS在中间宿主中存在核受体CAR/PXR-CYP酶介导的自身诱导代谢，这与其用后高复发密切相关；体外代谢研究确认疟原虫体内存在类CYP代谢酶（pCYP），且QHS联合CYP抑制剂可抗疟增效。为揭示疟原虫对QHS耐药的代谢调节机制，本项目将深入研究1）恶性疟原虫（敏感株和耐药株）在红内期不同生长阶段对QHS的代谢消除差异；2）约氏疟原虫对QHS在宿主小鼠体内自身诱导代谢的调控，以及小鼠肝代谢酶活性/表达的变化；3）疟原虫pCYP酶的底物选择性、抑制剂和诱导剂，并考察QHS联合pCYP酶抑制剂对延缓疟原虫耐药的作用。这将为最终阐明该类药物的耐药机制提供新思路，并为新型抗疟药的研发提供新靶点。

Plasmodium falciparum has become resistant to artemisinin antimalarials (Qing-hao-su; QHSs) in Southeast Asia. The resistant parasites exhibit altered patterns of development, which result in increased exposure to drugs at the most resistant stage of development (rings) in erythrocytes. Most studies on QHSs metabolism were mainly performed in intermediate hosts; however, there is no information on QHS metabolism in plasmodium, and the regulation mechanism of plasmodium on QHS metabolism in intermediate hosts remains unclear . In previous studies, we found that auto-induction metabolism (mediated by nuclear receptors CAR/PXR-CYP450 enzymes) exists for QHS drugs in intermediate hosts, which is related to high risk of recrudescence. In addition, CYP-like metabolic enzymes existed in Plasmodium falciparum cultured in vitro. Improved antimalarial potency was found for QHS in combination with CYP inhibitors. In order to elucidate the metabolic regulation mechanism in artemisinin resistance, the present project will focus on: 1) the difference of QHSs metabolic clearance in Plasmodium falciparum (drug sensitive strain and drug resistant strain) at different stages of development (rings, trophozoites and schizonts) using Plasmodium falciparum cultured in vitro; 2) the effect of Plasmodium yoelii (P. yoelii) on QHS auto-induction metabolism in P. yoelii-infected mice as an intermediate host, and the changes of the activities/mRNA expression of hepatic P450 enzymes of infected mice after multiple doses of QHSs; 3) the substrate selectivity, inhibitors and inducers of CYP-like enzymes (pCYPs), and the potency of QHSs in combination with pCYP inhibitors to delay the development of artemisinin resistance. The results will help to elucidate the molecular mechanism of artemisinin resistance and provide new targets for development of new antimalarials.