前言

Size: px

Start display at page:

Download "前言"

拟滇麴
5 years ago
Views:

1 CYPA4 CYPA4 CYPA P-450 CYPA nonconjugation) CYP 0 Relling et al., 994) CYP 70 Toffoli G, 994) CYPA 50 ~70 CYPA Hendrics et al., 99; Wils et al., 994; Wacher et al., 995) CYPA CYPA4 Borst et al., 99; parreboo et al., 997) Fojo et al., 987; Thiebaut et al., 987; Borst et al., 99; Wacher et al., 995; parreboo et al., 997; Wacher et al., 998) Murray et al., 988) Wu et al., 995; Fitzsions and Collins, 997; i et al., 998) Wacher et al., 998)) CYPA 0 ~50 Toffoli et al., 994 Fitzsions and Collins, 997) Wacher et al., 998) chuetz et al., 996a)) CYPA CYPA 4

2 Wacher et al., 998) CYPA4 cdna Fricer et al., 996) CYPA4 CYPA4 CYPA4 0 Duchare et al., 995a; Duchare et al., 995b) Gupta erythroycin cyclosporin Lown et al., 997a; Lown et al., 997b) Goez etoconazole 56 cyclosporine hiada et al., 994b) eog cyclosporin etoconzole 500 Watins et al., 987) toposide CYPA4 O-deethylation Benet et al., 996) CYPA4 etoconazole etoposide AUC 44 Prinson et al., ) CYPA4 ) P- P- 4

3 P- P- Gonzalez et al., 988a; Gonzalez et al., 988b; Aoyaa et al., 989b; Aoyaa et al., 989a; Aoyaa et al., 989c; Hashioto et al., 99) P- Hashioto et al., 99) P- etoposide Benet et al., 996) doxrubicin chuetz et al., 989) paclitaxel Wrighton and lswic, 989) topotecan Wrighton et al., 990) vinorelbine Wrighton et al., 990; olars et al., 994a; olars et al., 994b) P- transporters P- paclitaxel docetaxel vinblastin Lown et al., 994; Mcinnon and McManus, 995) an Asperen P- DZ PC 8 paclitaxel P- paclitaxel AUC 0 P- quinidine verapail DZ PC 8 4

4 CYPA P-Glycoprotein Aoyaa T et al., Molecular Carcinogenesis :9-98, 989) CYPA P- Aoyaa et al., 989a; Harris et al., 994; Wacher et al., 995; Lown et al., 997a; Paine et al., 997) CYPA4 P- cyclosporine Aoyaa et al., 989c; de Waziers et al., 990) sequinavir Lown et al., 997a; Lown et al., 998) etoposide Benet et al., 996) paclitaxel chuetz et al., 989) vinorelbine olars et al., 994b) P- CYPA4 P- CYPA Guengerich et al., 99) CYPA P- P- CYPA Walins 44

5 cyclosporine 50 CYPA cyclosporine de Waziers et al., 990) Fricer cyclosporine P- cyclosporine Goez et al., 995) cyclosporine P- RNA P- CYPA P- CYPA cyclosporine eogh et al., 995) CYP CYP RNA) CYPA CYPD6 P- CYPA P- CYPA CYPA P- CYP fatty acid steroid prostagladins glucocorticoids retinoids leuootrienes CYP Hellriegel 45

6 Hellriegel et al., 996) etoconazole, fluconazole, clotriazole, icronazole, erythroycin, 7-α-ethynylestradiol, tri-acetyloleandoycin, gestodene quinine Watins et al., 990) CYPA P-gp CYPA4 / P- 46

7 CYPA P-450 catalytic cycle) -5 CYP450 ) )hee-group hee group prosthetic group) )CYP450 reductase Fe ) 酶 CYP450 reductase) electron transfer) Fe ) Fe ) oxygen binding) Fe ) ferrous- oxy-substrate 酶 inhibition) induction) activation) Hollenberg et al., 00) P

8 P-450 isoenzye binding affinity) hee-group etoconazole Fluconazole iidazole hee-group Zhang et al., 00) CYP450 reductase CYP450 CYP450 CYP450 isoenzye ) copetitive inhibition) ) noncopetitive inhibition) ) uncopetitive inhibition) ) product 48

9 inhibition) ) transition-state analogs inhibition) ) slow, tight binding inhibitors) ) irreversible inhibitors) Guengerich, 999) Ortiz and MA, 995) reversible inhibition) 酶 quasi-irreversible inhibition) 酶酶 hee prosthetic group) quasi-irreversible coplex) irreversible inhibition) 酶酶酶酶 echanis-based inactivators) Ortiz and MA, 995) 49

10 J.H.Lin et al., 000) ) copetitive inhibition) ) noncopetitive inhibition) ) uncopetitive inhibition) CYP ax ) ) dose-dependent) Lineweaver-Bur plot /v vs. /) Dixon plot /v vs. ) ax egel, 975) weighting) nonlinear regression progra) Bronson et al., 995) 酶 Blac et al., 996; Renwic, 00) dose and tie dependent) 酶 50

11 ) 酶 - - 酶 ax ) ax / intrinsic clearance) inducer) transcription) RNA) translation) P-450 CYP Palaanda et al., 000) inducer DNA transcription 0-8 DNA DNA RNA degradation) CYP450 isoenzye CYPA/, C9, C9, A4 5

12 Phenobarbital Rifapicin, Clofibric acid, Pregnenolone DDT, chlordane, allylisopropylacetaide ax ) Mechaelis-Menten quation ax M ) ) hee-group ) CYP450 reductase CYP450 4) 5) 6) CYPA. CYPA. 5

13 CYPA 5

14 Mchaelis-Menten P P P a. :, ) d ) dt b. : P P ) d ) dt c. : ) d d ) dt dt d. ) ) ) Michaelis-Menten equation ) 4) ) T, T - 54

15 ) 4) 5) T..5) ) Michaelis-Menten equation: dp dt T dp dt T v, ax T )/ Michaelis-Menten equation : v ax.6) ax Mchaelis-Menten v 7) v....8) ax total 9) a. 6) v ax b. 6) 55

16 ax v ph affinity) ) ax turnover nuber) ax. : copetitive inhibition) non- copetitive inhibition) un-copetitive inhibition) 56

17 copetitive inhibition) s p P P : i i dp v...0) dt d )...) dt ) i i i i ) 57

18 ...) ) ) ) ) ) ) 0 ) ) 0 ) ) 0 ) 0 ) 0 ) ) 0 ) ) ) ) ) ) ) ) ) ) 0) ) ) dt dp o, i i ) ) dt dp i ax 58

19 ) ax i copetitive inhibition) ax and ) ax i.) ax ax x i 4) ax ) ) ax ax i ) i.5) 59

20 Models of copetitive inhibition and are utually exclusive. ) Classical odel. and coplete for the sae binding site. ust reseble structurally. ) and are utually exclusive because of steric hinderance. ) and share a coon binding group on the enzye. 4) The binding sites for and are distinct, but overlapping. 5) The binding of to a distinct inhibitor site causes a conforational change in the enzye that distorts or ass the substrate binding site and vice versa). 60

21 Michalis-Menten transforations equation. non-copetitive inhibition) s P P s P 6

22 : total total v p v total v p 9) ax total total v s ax s s s v ax...6) ax ax v..7) ) v ax ax.8) ax 6

23 5-5 Noncopetitive inhibition: and are not utually exclusive but is catalytically inactive. When binds, the enzye undergoes a conforational change which aligns the catalytic center, C, with the susceptible bonds of ; interferes with the conforational change, but has no effect on binding. un-copetitive inhibition) s p P P : 6

24 total total v p v total v p total 9) ax total s s s v ax s v ax 9) ax v..0) v ax ax..) ax 64

25 Uncopetitive inhibition binds only to the coplex. When binds, a conforational change occurs in the enzye which fors or unass the site. The resulting coplex is catalytically inactive C represents the catalytic center of the enzye. ax. v v Michaelis-Menten equation ax. v v / Lineweaver-Bur v ax x Y ax b v ax nax Y l/ ax X / 65

26 B /v l/ Lineweaver-Bur ) copetitive inhibition) Lineweaver-Bur Y x i ax / ax ax X ) ) non-copetitive inhibition) v ax ax Lineweaver-Bur Y X / v ) un-copetitive inhibition) v ax ax ax v ax X / Lineweaver-Bur Y ) 66

27 Double reciprocal /v verus /) Lineweaver-Bur plot. The range chosen is optial for the deterination of and ax Lineweaver-Bur plot /v / ) 67

28 Lineweaver-Bur plot 68

微生物酵素就是益生菌加酵素的高科技產品, 目前一種益生菌複合酶的生產方法已經獲得國家發明專利微生物酵素, 是適應生物養生而生產出來的, 因此起到了引領時代潮流,

微生物酵素就是益生菌加酵素的高科技產品, 目前一種益生菌複合酶的生產方法已經獲得國家發明專利微生物酵素, 是適應生物養生而生產出來的, 因此起到了引領時代潮流, 微生物酵素 - 概述微生物酵素就是含有多種活性益生菌的生物酶它能迅速到達人體內提前老化和菌群失調的區域, 活化再生細胞, 平衡腸道菌群, 維護黏膜免疫屏障, 抑制各種有害菌的產生和孳長, 促進人體長期保持年輕健康的狀態簡