Effects of the intramolecular hydrogen bond of taxoids on their interactions with cytochrome P450s
会议名称：《中国药理学会临床药理学专业委员会会议暨第十次全国临床药理学学术会议》
会议日期：2007年
学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学]
关 键 词：Paclitaxel 7-epi-Taxol 7-epi-10-deacetyl-Taxol chiral metabolism cytochrome P450
摘 要：AIM:Previous studies identify that C7-OH epimers of taxoids are the thermodynamically more stable isomers due to the strong hydrogen bonding of the C7α-OH to the C4α- acetate acyl *** order to understand the effects of certain structure modification on taxoids’ interactions with human hepatic cytochromes P450 better,the present study attempts to clarify the identity of the CYPs involved in 7- epi-Taxol,7-epi-10-Deacetyl’-Taxol,and their corresipond- ing C7β-*** metabolism and the underlying mech- anisms are also to investigate. METHODS:LC/MS/MS was used to identify the struc- tures of various taxoids metabolites by human liver micro- *** were conducted with CYP isoform spe- cific inhibitors and recombinant human CYP isofonns to as- cribe individual reaction to a single CYP isoform. RESULTS:Two monohydroxylated metabolites(M-1 and M-2)of 7-epi-Taxol were detected by LC/MS,and C3’ (M-1),C6(M-2)were proposed as the possible hydroxy- lation sites.7-epi-10-Deacetyl-Taxol was hydroxylated at C6 by human liver microsomes thus making M-3 as the unique primary *** inhibition studies and assays with recombinant human CYPs indicated that C3’ (M-1)was generated predominantly by CYP3A4 and C6 (M-2,M-3)by *** with the formation of C6-OH-majorepi-Taxol decreased significantlympounds among all chemotherapeutic drugs,Paclitaxel,the K for C6-hydroxylation of 7-epi-Taxol decreased significantly(13 versus 3μmol/L,8.5 versus 1.7μmol/L)by human liver microsomes and recombinant human ***, the overall metabolism of 7-epi-10-Deacetyl-Taxol in- creased to 20% in contrast with the low biotransformation rate of 10-deacetyl-Taxol(less than 0.8%). CONCLUSION:These findings suggest the distinct 3D conformation change of taxoids caused by the intromolecu- lar hydrogen bonding may attribute a major role in the sub- strate recognition by CYP2C8 and lead C-6 of taxoids more accessible to the active site.