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第十一章 遗传药理学及临床合理用药. 第一节 概 述. “ 伯氨喹溶血症 ” 在非洲黑人中较白种人更常见 ?. 这一不良反应与葡萄糖 -6- 磷酸脱氢酶( G-6-PD )缺乏导致对伯氨喹敏感的红细胞内谷胱甘肽浓度降低有关。. 是由于某些病人血浆胆碱酯酶灭活减慢,作用增强并延长的缘故。. 许多病人口服异烟肼发生外周 神经炎 ?. 现在可以将其归因于乙酰化酶缺陷者对诸如异烟肼、普鲁卡因胺和苯肼哒嗪等氧化性药物的不良反应。. 对肌松药琥珀胆碱的异常反应(呼吸肌麻痹甚至死亡) ?. 遗传药理学 ( Pharmacogenetics). - PowerPoint PPT Presentation
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**
-6-G-6-PD **
*(Pharmacogenetics)*
*1957Mostusky,1959Friedrich Vogel1962Kalow1973(WHO)*
*P450SNPs2090Human Genome ProjectHGPHGP*
* *
*DNADNA2322(autosome)(sex chromosome)DNA(allele)*
*(genotype)S
(phenotype) *
*, *
**
**
**
**
**P450(CYP450)CYP450
*-50P450 123CYP1CYP2 CYP3P450 *
Nelson1993P450P45040%CYPCYP255%CYP2DP450individualCYP2D6DalyCYP2D6CYP2D6*CYP2D6*6A **
**
* CYPlA2CYP450
17- P4501A2 ( CYP1A2*
*CYPlA2157.8kb76CYPlA215CYPlA2*1FCYPlA20.67CYPlA2*
*CYPlA2
CYPlA2C734A*
*CYP2C9CYP2C9 P4502C9 ( CYP2C9*
* CYP2C910CYP2C9*32.1~4.5 *
*P4502C19 ( CYP2C19CYP2C19 P450S-S-4-
CYP2C1910(10q241-10q24.3)14 *
*CYP2C19*2 CYP2C19*3
CYP2C19*2(25%)(13%)
CYP2C19*38%1%*
*P4502D6(CYP2D6)CYP1%~2% 80 CYP2D6 4-(EM)(PM)*
*CYP2D6 5070(PM)CYP2D6 PM 5%~10% 1%36%( IM)CYP2D6*10 58% *
* CYP2D622CYP2D6*3ACYP2D6*4A*4BCYP2D6*5CYP2D6*6APMPMCYP2D6CYP2D6 *
*CYP3A4 CYP450CYP3A4 ()DNA P4503A4 (CYP3A4)*
*NAT2 N-(N-acetyltransferaseNAT)N- NAT *
*,
10~30%40~70%
*
*
*
*N-N-acetyltransferase, NATNAT1NAT2NAT2NAT1*
*NAT2NAT2NAT2*49NAT2NAT2*4NAT2*4 *
* 30~5070~8095% *
**
**
**
*2NATlNATlNAT287NATlNAT2NAT1NATl*10NAT1NATl* 10*
*() ()(ADH) 4kDADH5*
ADH5ADHADHADHsADHsADHs
**
*(ALDH) ALDHALDH7ALDHALDHlALDH2ALDHs *
*ALDH2ALDH
*
**ALDH2
**
*-6- -6-(Glucose 6-phosphatedehydrogenaseG6PD)G6PDXG6PD(GSH) *
*G6PDNADPHGSH()H202GSHG6PDG6PD *
*TPMTTMT-OCOMT*
*-OCOMTO-COMT25%50%COMT22q11.1~q11.26COMT*
*(thlopurina methyl-transferaseTPMT)(thlopurina methyl-transferaseTPMT)6-(6-MP)TPMT 6-MP10~15 6-MP *
*MDRI P-P-ATP *
*P-MDRIC3435T P-3435CC P-AUC3435TT 3435CC55%3435TT 20%*
**
*>1%*
Ser49GlyGly389Arg1 Ser49GlyGly389Arg 389Arg**
1 2 2 16 (Gly-16Arg) Gly16Arg165.32.3
**
*(ACE)ACE ACE ACE 16 ACE I AT1RA1166C *
* *
* *
*77q3170508()(F508)F50870~9050 *
*24(cystic fibrosis transmembrane conductance regulatorCFTR)ATPCFTR3(F508)ATPCFTR*
*Ca2+ Ca2+Ca2+ATP*
*Ca2+*
* 198825*
*
5*
*K KKKK
*
**
*, ;40genetic locuspedigree(nortriptyline)identical twinfraternal twinheredity coefficient,heritability
h01010.880.98
N-(genetic polymorphismP-450(debrisoquine)(extensive metabolizerEM)(poor metabolizer, PM)DNADNAmRNAS-N-
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