第十一章 遗传药理学及临床合理用药
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Transcript of 第十一章 遗传药理学及临床合理用药
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**
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-6-G-6-PD **
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*(Pharmacogenetics)*
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*1957Mostusky,1959Friedrich Vogel1962Kalow1973(WHO)*
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*P450SNPs2090Human Genome ProjectHGPHGP*
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* *
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*DNADNA2322(autosome)(sex chromosome)DNA(allele)*
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*(genotype)S
(phenotype) *
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*, *
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**P450(CYP450)CYP450
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*-50P450 123CYP1CYP2 CYP3P450 *
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Nelson1993P450P45040%CYPCYP255%CYP2DP450individualCYP2D6DalyCYP2D6CYP2D6*CYP2D6*6A **
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* CYPlA2CYP450
17- P4501A2 ( CYP1A2*
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*CYPlA2157.8kb76CYPlA215CYPlA2*1FCYPlA20.67CYPlA2*
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*CYPlA2
CYPlA2C734A*
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*CYP2C9CYP2C9 P4502C9 ( CYP2C9*
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* CYP2C910CYP2C9*32.1~4.5 *
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*P4502C19 ( CYP2C19CYP2C19 P450S-S-4-
CYP2C1910(10q241-10q24.3)14 *
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*CYP2C19*2 CYP2C19*3
CYP2C19*2(25%)(13%)
CYP2C19*38%1%*
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*P4502D6(CYP2D6)CYP1%~2% 80 CYP2D6 4-(EM)(PM)*
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*CYP2D6 5070(PM)CYP2D6 PM 5%~10% 1%36%( IM)CYP2D6*10 58% *
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* CYP2D622CYP2D6*3ACYP2D6*4A*4BCYP2D6*5CYP2D6*6APMPMCYP2D6CYP2D6 *
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*CYP3A4 CYP450CYP3A4 ()DNA P4503A4 (CYP3A4)*
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*NAT2 N-(N-acetyltransferaseNAT)N- NAT *
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*,
10~30%40~70%
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*N-N-acetyltransferase, NATNAT1NAT2NAT2NAT1*
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*NAT2NAT2NAT2*49NAT2NAT2*4NAT2*4 *
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* 30~5070~8095% *
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*2NATlNATlNAT287NATlNAT2NAT1NATl*10NAT1NATl* 10*
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*() ()(ADH) 4kDADH5*
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ADH5ADHADHADHsADHsADHs
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*(ALDH) ALDHALDH7ALDHALDHlALDH2ALDHs *
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*ALDH2ALDH
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**ALDH2
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*-6- -6-(Glucose 6-phosphatedehydrogenaseG6PD)G6PDXG6PD(GSH) *
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*G6PDNADPHGSH()H202GSHG6PDG6PD *
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*TPMTTMT-OCOMT*
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*-OCOMTO-COMT25%50%COMT22q11.1~q11.26COMT*
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*(thlopurina methyl-transferaseTPMT)(thlopurina methyl-transferaseTPMT)6-(6-MP)TPMT 6-MP10~15 6-MP *
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*MDRI P-P-ATP *
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*P-MDRIC3435T P-3435CC P-AUC3435TT 3435CC55%3435TT 20%*
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*>1%*
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Ser49GlyGly389Arg1 Ser49GlyGly389Arg 389Arg**
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1 2 2 16 (Gly-16Arg) Gly16Arg165.32.3
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*(ACE)ACE ACE ACE 16 ACE I AT1RA1166C *
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* *
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*77q3170508()(F508)F50870~9050 *
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*24(cystic fibrosis transmembrane conductance regulatorCFTR)ATPCFTR3(F508)ATPCFTR*
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*Ca2+ Ca2+Ca2+ATP*
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*Ca2+*
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* 198825*
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5*
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*K KKKK
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*, ;40genetic locuspedigree(nortriptyline)identical twinfraternal twinheredity coefficient,heritability
h01010.880.98
N-(genetic polymorphismP-450(debrisoquine)(extensive metabolizerEM)(poor metabolizer, PM)DNADNAmRNAS-N-