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	Overlapping Substrate and Inhibitor Specificities of Human Cytochrome P450 2C8 and 3A4; 人体细胞色素P4502C8及3A4底物及抑制剂的重叠性
	Yang L(杨凌) ; Zhang YY(张延延)
	2010-05-16
会议名称	18th international symposium on microsomes and drug oxidations
会议日期	2010-5-16
会议地点	中国
其他题名	人体细胞色素p4502c8及3a4底物及抑制剂的重叠性
页码	96/2
通讯作者	杨凌
中文摘要	overlapping substrate and inhibitor specificities of human cytochrome p450 2c8 and 3a4 ling yang, yan-yan zhang laboratory of pharmaceutical resource discovery, dalian institute of chemical physics, chinese academy of sciences, 457 zhongshan road, dalian, 116023 china background: human cytochrome p450 (cyp) 2c8 and 3a4 have broad capacity to metabolize structurally diverse drugs. the crystallographic studies indicate that the active site volume of cyp2c8 is similar to that of cyp3a4, but the shapes of the cavities differ considerably. although cyp2c8 and 3a4 share only 25% sequence homology, there appears to be substantial overlapping substrate and inhibitor specificities. better understanding of the structural requirements for dual interaction of drugs with both cyps could provide vital information for optimizing pharmacokinetic behavior, as well as for interpretation of in vivo data. for this reason, structure-metabolism relationships study was performed on a series of model compounds, including 6 paclitaxel derivatives and 7 schisandra lignans. results: (1) the “northern hemisphere” and c-3’ part of taxane molecule had major consequence on its interactions with cyp2c8 and 3a4 (zhang et al., 2009b). the presence of an alkyl group at c-3’ significantly increased the c-13 lateral chain mono-hydroxylation of taxanes by cyp3a4 (zhang et al., 2008). however, when taxanes contained c-7α hydroxyl, cyp2c8 showed higher catalytic efficiency of taxane ring hydroxylation (zhang et al., 2009a). the absence of an acetyl group in c-10 severely impaired the overall biotransformation supported by cyps. (2) the presence of one methylenedioxy ring in dibenzocyclooctadiene lignans from fructus schisandrae could enhance both cyp2c8 and 3a4 inhibitory activity. the introduction of another methylenedioxy ring remarkably abolished its inhibitory effect on cyp2c8, although little impact on cyp3a4 inhibition activity was observed. conclusions: all these findings collectively suggest that the interactions of drugs with cyps should be studied in the context of whole molecular framework. the metabolic stabilities of taxanes result from composite effects of various structural moieties, including c-7 configuration, c-3’ and c-10 substituent. methylenedioxy ring represents one of the most important structural determinants in the inhibition potential of schisandra lignans on both cyp2c8 and 3a4. references: zhang jw, ge gb, liu y, wang lm, liu xb, zhang yy, li w, he yq, wang zt, sun j, xiao hb, yang l. drug metabolism and disposition 2008; 36(2): 418-426. zhang yy, liu, y, zhang jw, ge gb; wang lm, sun j, yang l. xenobiotica 2009a; 39(4): 283–292. zhang yy, liu y, zhang jw, ge gb, liu hx, wang lm, sun j, yang l. xenobiotica 2009b; doi: 10.3109/00498250903271989.
会议主办者	issx学会
学科主题	物理化学
语种	中文
内容类型	会议论文
源URL	[http://159.226.238.44/handle/321008/114184]
专题	大连化学物理研究所_中国科学院大连化学物理研究所
推荐引用方式 GB/T 7714	Yang L,Zhang YY. Overlapping Substrate and Inhibitor Specificities of Human Cytochrome P450 2C8 and 3A4, 人体细胞色素P4502C8及3A4底物及抑制剂的重叠性[C]. 见:18th international symposium on microsomes and drug oxidations. 中国. 2010-5-16.

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