Metabolism of Non-nutritive Material

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?11?
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Metabolism of Non-nutritive Material
??????????? ??? yuanyuanch_at_njmu.edu.cn
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Biotransformation in the Liver
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????????
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(biotransformation)?
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????????? ???????????,?????????????????????? ?
??????? ????????? (xenobiotics)????,????
(inactivate),??? (detoxicate)??????????????????,?
??????
? ????????????? (detoxification)
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????????????,???????,??????????????,??????,??????
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1.?????????????????
1) ????P450????
????P450????????????????
????????(?????) ??Cyt P450,NADPHH,
NADPH-???? P450??? ??????? RHO2NADPHH
? ROHNADPH2O
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(No Transcript)
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???? (???)
????-S- ???????
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2) ??-????
??-????????????????????????

• ??-???? (flavin containing monooxygenase,
  FMO)???NADPH?FAD???,??????????????????????????????
  ?????
• ?????????FMO???,???FMO3?FMO4?FMO5???,FMO3????????F
  MO????70?90?FMO1???????

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??-????????
S S-O
FAD-OOH FMO NADP
O2
FAD-OH FMO NADP
FADH2 FMO NADP
H2O
FAD FMO NADP
FAD FMO NADPH
FAD FMO
NADP
NADPH
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????
????
?????
N-???????
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3) ?????
????? (monoamine oxidase, MAO)????????????
????????
?????
????
????
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3,4,5-???????
????
3,4,5-???????
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4) ?????????
??????????????????
???????
?????
???? (alcohol dehydrogenase, ADH)????????
CH3CH2OH NAD ??? CH3CHO NADH H
???? (aldehyde dehydrogenase, ALDH)???????
CH3CHO NAD H2O ??? CH3COOH NADH H
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ADH??????????ALDH2????,??????????????,????????????
?????????????
???????????????????????????CYP2E1???????mRNA???,??
?????????? (microsomal ethanol oxidizing system,
MEOS)?CYP2E1??????????ADPH??,??????????,??????????
?????????????????
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5) ?????????????
?????? (nitroreductase)???????(azoreductase)??I???
???????
????????
?????
??? ???? ??? ???
?????
??? ??????
N-???????
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6) ??????????????
?? (esterases)???? (amidase)???????? (epoxide
hydrolase)???????????
??????????????
?????
?????????????????,???????????? ???????????? ??????
?????????????,????????????,???????????????????
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????????
?????
???
???
?
???
???-7,8-??
DHEP-BP
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2.??????????
?????????????????????????????????
??????????????????????????????????
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1) ?????????
????????????????????
???????????????????
(UDPGA)
HOCH2 ? ?
COOH ? ?
2NADH 2H
O
O
2NAD
H ? ? ? OH
H ? ? ? OUDP
H ? ? ? OH
H ? ? ? OUDP
OH ? ? ? H
OH ? ? ? H
UDPG???
? ? OH
? ? OH
UDPG
UDPGA
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??? ???????? (UDP-glucuronyl transferases, UGT)
????????
??
COOH ? C ? H
O
O
H ? C ? HO
C
UGT
UDPGA
OH ? C ? H
H ? C ? OH
OH
UDP
H
??
???????
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2) ?????????????
????3?-????5?-???? (PAPS)
????????? (sulfotransferase, SULT)
???????
??
O
O
PAPS
PAP
HO3SO
HO
??
?????
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3) ????????
????????GSH ???????S-??? (glutathione
S-transferase, GST) ???????
????B1-8,9- ????
???????? ????
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4) ????????????????
???
???CoA
???
???CoA
??????
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5) ??????????????????
????S?????? (SAM) ??????????
CONH2
CONH2
?????
S-??????
S-????????
N ? CH3
N
????
N-??????
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6) ????????????????????
??????CoA ????????? ???????
CH3COCoA
HSCoA
???
????A
?????
??A
??
N-????
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?.?????????
(?)????????????????? ?????
(?)????????????????? (???)

• (?)?????????????????

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2??????????
?????????
????????????????????CYP?UGT???,???????????????????

??????????
??????????????? (aryl hydrocarbons hydroxylase,
AHH)???
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(?)?????????????????
?????????????????????????????????
?????????????????????????????????????????????????
??????
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(?)????????????
1.??????????????? 2.????????????????? 3.?????????
?????? 4.????????????? 5.??????????????
6.???????????????
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???
?????????
Metabolism of Bile and Bile Acids
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???????????????
????
??? (hepatic bile)
???? (gallbladder bile)
?????
????????
????? ???? (bile salts)????????????????????????
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??
(???)
????? ? ??? ? ?????
? ??????? ?
??? ? ???
(????)
?????? ????(????)?????(??????????????????)??????
39
??????????????
??? ????
?? 1.009?1.013 1.026?1.032
pH 7.1?8.5 5.5?7.7
? 96?97 80?86
???? 3?4 14?20
??? 0.2?0.9 0.5?1.1
??? 0.1?0.9 1?4
???? 0.5?2 1.5?10
??? 0.05?0.17 0.2?1.5
??? 0.1?0.5 1.8?4.7
??? 0.05?0.17 0.2?0.9
?? 0.05?0.08 0.2?0.5
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???????? ?????????????/???
????
??????????????????? ???????????????????
????
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?????
??
?????
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?????
CONHCH2CH2SO3H
OH
12
?????
3
7
HO
OH
H
CONHCH2COOH
OH
12
?????
7
3
HO
OH
H
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????? ???????????????????,????????????????????
????? ?????????????7?-???????????,???????????
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?????
COOH
OH
12
??
3
7
HO
OH
H
COOH
OH
7?-????
12
????
3
7
HO
H
?????
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?????
COOH
12
?????
7
3
HO
OH
H
7?-????
COOH
12
???
7
3
?????
HO
H
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????????
??? (bile acids)??? ??????????????????,???????????
,?????,?????? (bile salts)? ?????????????????????
???????
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??????????(?????)
?????????????
???
?????????
???
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?????,??????????? ??????????????????? ? 101?
?????????????
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??????????
?????????????????
????????(enterohepatic circulation of bile acid)
???????????,?????????????,????????????,???????????
??
???? (bile acid pool)
???????????,???????3?5g?
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??????????????
?????????,??????????????????????????????????????,?
???????????,????????98?????????????,?????????????
???????Na????????? (apical sodium-dependent bile
salt transporter, ASBT)????????
????????????????????
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? ? ? ? ? ? ? ? ? ?
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????????????0.40.6g,???????????35g,?????????,???
??????612?????,???1232g????
????????????
1.??????????????????? 2.??????????,?????????
????? 3.????/????????,???????
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????????????????
(?)??????????
(?)?????????????????? ???????????
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???(gallstone)
????? (cholesterol stone)
??????????50 ????? (black pigment stone)
???????????1030 ????? (brown pigment
stone) ??????????
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???
????????
Biosynthesis of Heme
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??? (heme) ??????????? (hemoprotein)???,??????????
?????????????,????? (hemoglobin, Hb)?????
(myoglobin)????? (cytochrome)??????
(catalase)??????(peroxidase)??
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????????
??
??????????,?????Fe2????? ??????????,
???????????? (porphyrinogens),??????
(porphyrin)????? ?????????,????,????,?????????????
?????? ?????????,??????????????? ????????,????????
?????????,??????,??????????? (porphyria)?
?
?
?
?
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(No Transcript)
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??????????
????? ??????????????????
??????????????
???????? ???????????? ?????????
????? ???????CoA?Fe2
60
????
1.?-??-?-??? (ALA)???
??????????????-??-?-??? (?- aminolevulinic acid,
ALA)?ALA?? (ALA synthase)??,???????????
???????
COOH ? H2C ? CH2 ?
CO ? CH2NH2
COOH ? H2C ? CH2 ?
CSCoA ? O
HSCoA CO2
CH2NH2 ? COOH

ALA?? (?????)
?????A
???
ALA
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2.???????
ALA???????????ALA????????????
COOH ? CH2 ?
CH2 ? OC ? HCH
? HNH
O
OH
COOH ? H2C ? CH2 ?
CO ? CH2 ? NH2
HO
O
N H
H2N
????(PBG)
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3.????????????
????????????????????
????????UPG I (???????)
4????
?????
????III???
????III???
?????
?????
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4.??????
????????III??????,?????
???????
????? ?????
?????
?????
????? ???
?????
????
???
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???
??
???
????
2
ALA
ALA
????
4
???
??? ?????A
3NH3
?????
???IX
NH3
2CO2 4H
CO2
????III
????III
????IX
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????????
? ?????????????,?????? ???? ?
??????????CoA????Fe2?
????? ? ???????????????????,
????????
66
???????
?????????????????? ???????????????,??????????
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????????????
1.ALA??
????????????,??????????, ????????,???????????, ???
??????, ?????????????
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2.?????ALA?????????
??????ALA???,???????????,????????????????,?????
???????(????)????????????(?????)?
3.??????? (erythropoietin, EPO)
???????????????????,????????,????? ??????,????????
??????? ?Hb???,??????????????
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???
?????????
Metabolism of Bile Pigments and Jaundice
70
??????????????????
??? (bile pigment)??????????????????,?????????????
?????
71
(?)?????????????
??? (bilirubin)?? ??????????????????????????????
??????
?80????????????????
72
(?)????????
?????????????????????
???????????-????????????????
??
????
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???
???
?????? ????,?????????
73
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CO??????,??????????????
74
(?)??????????????????
????????????????????????,??????????????????,??????
??????,?????????????,?????????????,???????? ??????
lt5?-???(?-????????),???????????????
75
?????
????
O
H
N
O
H
C
O
98
H
N
N
H
O
H
N
C
O
H
O
???????????
???????
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(?)?????????????
1.???????????????????
CO????????????????????,??cGMP????
2.??????????
???????????????????,???????????????
77
(No Transcript)
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???? ?????????????,???????????????????
????? ????,???,????
79
????????????????????, ????????,????????????
????????????????????? ??,???????????????????
??????/????/????? ????????,????????????????,??????
???
80
?????????????????????????

• (?)????????????????

???????????????????????????,???????? ?????????????
???? ?????????-??????????????????????
81
Y???Z???????????
??????????????Y???Z?????,???Y????? Y??,?????
(ligandin)???????????????
82
(?)???????????
?????????? ??????(???????UDP????
?,UDPGA) ?????????? ??????????????,????
???????????????, ????????
83
??????????
????????? UDPGA
??? UDPGA
UDP-????????
UDP-????????
????????? UDP
????????? UDP
84
????????????
H
H
H
H
H N
H N
H N
H N
O
O
? CH2 ? CH2 ? CO ? O ? ? ? ? H
? CH2 ? CH2 ? CO ? O ? ? ? ? H
HOOC ? H
COOH ? H
O
O
H ? ? OH
H ? ? OH
OH ? ? H
H ? ? HO
OH ? ? H
H ? ? HO
85
???
2UDP-????
UDP-????????
2UDP
????????
86
????????????
? ? ????? ?????
? ? ????? ???? ????? ????
??????? ??? ??
??????? ?????? ??????
????? ? ?
??? ? ?
??????? ? ?
?????? ?? ?
???????? ???? ? ?
87
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???????????????,??????????,???????????????????,???
?????????????,?????????
88
(?)????????????????
???????????????????????
???????2 (MRP2)?????????????????????
89
??????????????????
??
?????
?????
????
? ?
???
??
???
??
???d-????,????,????
??d-???,i-???,???
90
(?)???????????
8 H
???
8 H
d-????
- 2 H
d-???
????(i-????)
4 H
- 2 H
??? (i-???)
?????? ?????
????(l-????)
- 2 H
P-CH2-CH2-COOH
??? (l-???)
91
(?)???????? (1020)
????????????????????,??????,?????????????,????????
?? (bilinogen enterohepatic circulation)?
92
??-????
??
???
? ? ? ? ? ? ? ? ? ?
???? ??? ??? ???
???
??
???
???-??? ???
Y?? Z??
???-Y?? ???-Z??
2O2 Fe3 H2O CO
NADPHH NADP
UDPGA UDP
???
???????
???? (MRP2)
NADPHH NADP
???
? ?
???(??)
???
?
??
???
???????
O2
O2
???
??
??
???
????
?
??
93
????????????????
???????????????
??????????????
94
????????????????
???????????3.4?17.1?mol/L (0.2?1mg/dl),??????????
????????????????,??????????????
??????????17.1?mol/L (1mg/dl)?????????
?????????,???????????????????,????????(jaundice)?
95
??
?????
??(????????????) 1.????? (hemolytic
jaundice) 2.????? (obstructive
jaundice) 3.?????? (hepatocellular jaundice)
96
??
1.????? (hemolytic jaundice)
??????????-?????????
?,???????,???????? ???????,?????????
???????
???????????????????? ?????
97
??
98
??
????? ?????
?????? ?
?????? ?
????? -
???? ????
???? -
??? ?
??? ?
??? ?
??? ?
99
??
2.?????? (hepatocellular jaundice)
???????????,???????? ?????????????
????????,??????????
100
??
101
??
?????? ??????
?????? ?
?????? ?
????? ?
???? ????
????
??? ???
??? ???
??? ????
??? ????
102
??
3.????? (obstructive jaundice)
?????????????,??????,
???????????????, ??????????,
????????????
????????(???)??????? ????????
103
??
104
??
????? ?????
?????? ?
?????? -
????? ??
???? ????
????
??? ?
??? ?
??? ??-
??? ?
105
??
????????????
?? ?? ????? ?????? ?????
?????
?? lt1mg/dl gt1mg/dl gt1mg/dl gt1mg/dl
????? ?? ? ??
????? 00.8 mg/dl ?? ?
???
???? - -
???? 04 mg/24 h ? ??? ?
??? ?? ? ??? ?
???? ?? ? ????? ????? ?????
?????, ??????
106
? ? ??
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,? ??????????? ?????????? ??????