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KEGG   PATHWAY: hsa04976
Entry
hsa04976                    Pathway                                
Name
Bile secretion - Homo sapiens (human)
Description
Bile is a vital secretion, essential for digestion and absorption of fats and fat-soluble vitamins in the small intestine. Moreover, bile is an important route of elimination for excess cholesterol and many waste product, bilirubin, drugs and toxic compounds. Bile secretion depends on the function of membrane transport systems in hepatocytes and cholangiocytes and on the structural and functional integrity of the biliary tree. The hepatocytes generate the so-called primary bile in their canaliculi. Cholangiocytes modify the canalicular bile by secretory and reabsorptive processes as bile passes through the bile ducts. The main solutes in bile are bile acids, which stimulate bile secretion osmotically, as well as facilitate the intestinal absorption of dietary lipids by their detergent properties. Bile acids are also important signalling molecules. Through the activation of nuclear receptors, they regulate their own synthesis and transport rates.
Class
Organismal Systems; Digestive system
Pathway map
hsa04976  Bile secretion
hsa04976

Drug
D00163  Chenodiol (USAN)
D00734  Ursodiol (USP)
D00893  Pravastatin sodium (JP18/USP)
D02021  Secretin (JAN/USAN/INN)
D06008  Tariquidar (USAN/INN)
D06387  Zosuquidar trihydrochloride (USAN)
D09360  Obeticholic acid (JAN/USAN/INN)
D09916  Ivacaftor (USAN/INN)
D10134  Lumacaftor (USAN/INN)
D10669  Sotagliflozin (USAN/INN)
D10685  Lumacaftor and ivacaftor
D10699  Cholic acid (JAN/USAN)
D10795  Elobixibat hydrate (JAN)
D10951  Maralixibat (USAN)
D10952  Maralixibat chloride (JAN/USAN/INN)
D11042  Tezacaftor and ivacaftor
D11539  Linerixibat (JAN/USAN)
D11548  Tropifexor (USAN)
D11700  Elexacaftor, ivacaftor and tezacaftor
D11716  Odevixibat (USAN)
D11724  Galicaftor (USAN/INN)
D12140  Navocaftor (USAN/INN)
D12454  Icenticaftor (USAN/INN)
D12718  Vanzacaftor (USAN/INN)
D12719  Vanzacaftor calcium (USAN)
Other DBs
GO: 0032782
Organism
Homo sapiens (human) [GN:hsa]
Gene
2052  EPHX1; epoxide hydrolase 1 [KO:K01253] [EC:3.3.2.9]
6579  SLCO1A2; solute carrier organic anion transporter family member 1A2 [KO:K03460]
28234  SLCO1B3; solute carrier organic anion transporter family member 1B3 [KO:K05043]
10599  SLCO1B1; solute carrier organic anion transporter family member 1B1 [KO:K05043]
115072896  SLCO1B3-SLCO1B7; SLCO1B3-SLCO1B7 readthrough [KO:K05043]
6554  SLC10A1; solute carrier family 10 member 1 [KO:K14341]
10864  SLC22A7; solute carrier family 22 member 7 [KO:K08204]
9376  SLC22A8; solute carrier family 22 member 8 [KO:K08205]
6580  SLC22A1; solute carrier family 22 member 1 [KO:K08198]
3156  HMGCR; 3-hydroxy-3-methylglutaryl-CoA reductase [KO:K00021] [EC:1.1.1.34]
949  SCARB1; scavenger receptor class B member 1 [KO:K13885]
3949  LDLR; low density lipoprotein receptor [KO:K12473]
57552  NCEH1; neutral cholesterol ester hydrolase 1 [KO:K14349] [EC:3.1.1.-]
1581  CYP7A1; cytochrome P450 family 7 subfamily A member 1 [KO:K00489] [EC:1.14.14.23]
9971  NR1H4; nuclear receptor subfamily 1 group H member 4 [KO:K08537]
6256  RXRA; retinoid X receptor alpha [KO:K08524]
8431  NR0B2; nuclear receptor subfamily 0 group B member 2 [KO:K08563]
10941  UGT2A1; UDP glucuronosyltransferase family 2 member A1 complex locus [KO:K00699] [EC:2.4.1.17]
79799  UGT2A3; UDP glucuronosyltransferase family 2 member A3 [KO:K00699] [EC:2.4.1.17]
7367  UGT2B17; UDP glucuronosyltransferase family 2 member B17 [KO:K00699] [EC:2.4.1.17]
10720  UGT2B11; UDP glucuronosyltransferase family 2 member B11 [KO:K00699] [EC:2.4.1.17]
54490  UGT2B28; UDP glucuronosyltransferase family 2 member B28 [KO:K00699] [EC:2.4.1.17]
54578  UGT1A6; UDP glucuronosyltransferase family 1 member A6 [KO:K00699] [EC:2.4.1.17]
54657  UGT1A4; UDP glucuronosyltransferase family 1 member A4 [KO:K00699] [EC:2.4.1.17]
54658  UGT1A1; UDP glucuronosyltransferase family 1 member A1 [KO:K00699] [EC:2.4.1.17]
54659  UGT1A3; UDP glucuronosyltransferase family 1 member A3 [KO:K00699] [EC:2.4.1.17]
7365  UGT2B10; UDP glucuronosyltransferase family 2 member B10 [KO:K00699] [EC:2.4.1.17]
54600  UGT1A9; UDP glucuronosyltransferase family 1 member A9 [KO:K00699] [EC:2.4.1.17]
7364  UGT2B7; UDP glucuronosyltransferase family 2 member B7 [KO:K00699] [EC:2.4.1.17]
54575  UGT1A10; UDP glucuronosyltransferase family 1 member A10 [KO:K00699] [EC:2.4.1.17]
54576  UGT1A8; UDP glucuronosyltransferase family 1 member A8 [KO:K00699] [EC:2.4.1.17]
54579  UGT1A5; UDP glucuronosyltransferase family 1 member A5 [KO:K00699] [EC:2.4.1.17]
7366  UGT2B15; UDP glucuronosyltransferase family 2 member B15 [KO:K00699] [EC:2.4.1.17]
54577  UGT1A7; UDP glucuronosyltransferase family 1 member A7 [KO:K00699] [EC:2.4.1.17]
7363  UGT2B4; UDP glucuronosyltransferase family 2 member B4 [KO:K00699] [EC:2.4.1.17]
574537  UGT2A2; UDP glucuronosyltransferase family 2 member A2 [KO:K00699] [EC:2.4.1.17]
6822  SULT2A1; sulfotransferase family 2A member 1 [KO:K11822] [EC:2.8.2.14]
10998  SLC27A5; solute carrier family 27 member 5 [KO:K08748] [EC:6.2.1.7]
570  BAAT; bile acid-CoA:amino acid N-acyltransferase [KO:K00659] [EC:2.3.1.65 3.1.2.2]
1576  CYP3A4; cytochrome P450 family 3 subfamily A member 4 [KO:K17689] [EC:1.14.13.32 1.14.14.55 1.14.14.56 1.14.14.57 1.14.14.73 1.14.14.-]
366  AQP9; aquaporin 9 [KO:K09877]
343  AQP8; aquaporin 8 [KO:K09869]
64240  ABCG5; ATP binding cassette subfamily G member 5 [KO:K05683]
64241  ABCG8; ATP binding cassette subfamily G member 8 [KO:K05684]
8647  ABCB11; ATP binding cassette subfamily B member 11 [KO:K05664]
1244  ABCC2; ATP binding cassette subfamily C member 2 [KO:K05666]
9429  ABCG2; ATP binding cassette subfamily G member 2 (JR blood group) [KO:K05681]
760  CA2; carbonic anhydrase 2 [KO:K18245] [EC:4.2.1.1]
6522  SLC4A2; solute carrier family 4 member 2 [KO:K13855]
5243  ABCB1; ATP binding cassette subfamily B member 1 [KO:K05658] [EC:7.6.2.2]
5244  ABCB4; ATP binding cassette subfamily B member 4 [KO:K05659] [EC:7.6.2.2]
6548  SLC9A1; solute carrier family 9 member A1 [KO:K05742]
57835  SLC4A5; solute carrier family 4 member 5 [KO:K13857]
8714  ABCC3; ATP binding cassette subfamily C member 3 [KO:K05667]
10257  ABCC4; ATP binding cassette subfamily C member 4 (PEL blood group) [KO:K05673]
200931  SLC51A; solute carrier family 51 member A [KO:K14360]
123264  SLC51B; SLC51 subunit beta [KO:K14361]
3781  KCNN2; potassium calcium-activated channel subfamily N member 2 [KO:K04943]
476  ATP1A1; ATPase Na+/K+ transporting subunit alpha 1 [KO:K01539] [EC:7.2.2.13]
477  ATP1A2; ATPase Na+/K+ transporting subunit alpha 2 [KO:K01539] [EC:7.2.2.13]
478  ATP1A3; ATPase Na+/K+ transporting subunit alpha 3 [KO:K01539] [EC:7.2.2.13]
480  ATP1A4; ATPase Na+/K+ transporting subunit alpha 4 [KO:K01539] [EC:7.2.2.13]
23439  ATP1B4; ATPase Na+/K+ transporting family member beta 4 [KO:K01540]
481  ATP1B1; ATPase Na+/K+ transporting subunit beta 1 [KO:K01540]
482  ATP1B2; ATPase Na+/K+ transporting subunit beta 2 [KO:K01540]
483  ATP1B3; ATPase Na+/K+ transporting subunit beta 3 [KO:K01540]
486  FXYD2; FXYD domain containing ion transport regulator 2 [KO:K01538]
6343  SCT; secretin [KO:K05263]
6344  SCTR; secretin receptor [KO:K04588]
2778  GNAS; GNAS complex locus [KO:K04632]
107  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
109  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
112  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
113  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
114  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
1080  CFTR; CF transmembrane conductance regulator [KO:K05031] [EC:5.6.1.6]
8671  SLC4A4; solute carrier family 4 member 4 [KO:K13575]
361  AQP4; aquaporin 4 [KO:K09866]
358  AQP1; aquaporin 1 (Colton blood group) [KO:K09864]
6555  SLC10A2; solute carrier family 10 member 2 [KO:K14342]
6523  SLC5A1; solute carrier family 5 member 1 [KO:K14158]
6550  SLC9A3; solute carrier family 9 member A3 [KO:K12040]
6513  SLC2A1; solute carrier family 2 member 1 [KO:K07299]
Compound
C00001  H2O
C00011  CO2
C00024  Acetyl-CoA
C00026  2-Oxoglutarate
C00031  D-Glucose
C00051  Glutathione
C00080  H+
C00114  Choline
C00187  Cholesterol
C00238  Potassium cation
C00288  HCO3-
C00315  Spermidine
C00318  L-Carnitine
C00366  Urate
C00486  Bilirubin
C00504  Folate
C00575  3',5'-Cyclic AMP
C00584  Prostaglandin E2
C00639  Prostaglandin F2alpha
C00695  Cholic acid
C00698  Cl-
C00735  Cortisol
C00750  Spermine
C00780  Serotonin
C00805  Salicylate
C00865  Phospholipid
C00942  3',5'-Cyclic GMP
C01330  Sodium cation
C01353  Carbonic acid
C01405  Aspirin
C01443  Ouabain
C01576  Etoposide
C01829  Thyroxine
C01844  Pravastatin
C01921  Glycocholate
C01937  Methotrexate
C01996  Acetylcholine
C02165  Leukotriene B4
C02166  Leukotriene C4
C02380  6-Mercaptopurine
C02465  Triiodothyronine
C02528  Chenodeoxycholate
C02530  Cholesterol ester
C02538  Estrone 3-sulfate
C02918  1-Methylnicotinamide
C03033  beta-D-Glucuronoside
C03642  Taurolithocholate sulfate
C03758  Dopamine
C03990  Lithocholic acid
C04483  Deoxycholic acid
C04555  Dehydroepiandrosterone sulfate
C05122  Taurocholate
C05371  Microcystin LR
C05465  Taurochenodeoxycholate
C05466  Glycochenodeoxycholate
C05503  Estradiol-17beta 3-glucuronide
C05551  Penicillin G
C05963  Thromboxane B2
C06526  Quinine
C06570  Tetracycline
C06688  Rifampicin
C06804  Acetaminophen
C06810  Aciclovir
C06880  Cefazolin
C06890  Ceftizoxime
C06956  Digoxin
C06999  Fexofenadine
C07014  Fluvastatin
C07051  Indinavir
C07065  Lamivudine
C07151  Metformin
C07184  Valacyclovir
C07185  Valproic acid
C07201  Vinblastine
C07207  Zalcitabine
C07210  Zidovudine
C07240  Ritonavir
C07394  Paclitaxel
C07512  Tetraethylammonium
C07649  5-FU
C07660  Levofloxacin
C07966  Cerivastatin
C08357  Estradiol-17beta 3-sulfate
C08439  Phalloidin
C09955  Ochratoxin A
C11158  Topotecan
C11231  Docetaxel anhydrous
C11245  Glucuronosyletoposide
C11277  Adefovir
C11310  1-Methyl-4-phenylpyridinium
C11363  Sulfobromophthalein
C11587  BQ 123
C11754  Cephaloridine
C12560  Saquinavir mesylate
C16114  Cholecystokinin-8
C16578  Morphine-6-glucuronide
C16643  Morphine-3-glucuronide
D00125  Etoposide (JP18/USP/INN)
D00140  Erythromycin (JP18/USP/INN)
D00142  Methotrexate (JP18/USP/INN)
D00184  Cyclosporine (USP)
D00186  Ciprofloxacin (JP18/USP/INN)
D00201  Tetracycline (JAN/USP/INN)
D00214  Dactinomycin (USP)
D00224  Allopurinol (JP18/USP/INN)
D00240  Aztreonam (JP18/USP/INN)
D00247  Bumetanide (JP18/USP/INN)
D00295  Cimetidine (JP18/USP/INN)
D00298  Digoxin (JP18/USP)
D00318  Famotidine (JP18/USP/INN)
D00331  Furosemide (JP18/USP/INN)
D00333  Ganciclovir (JAN/USP/INN)
D00340  Hydrochlorothiazide (JP18/USP/INN)
D00353  Lamivudine (JAN/USP/INN)
D00359  Lovastatin (USP/INN)
D00400  Valsartan (JP18/USP/INN)
D00422  Ranitidine (USAN/INN)
D00427  Ritonavir (JAN/USP/INN)
D00429  Saquinavir (JAN/USP/INN)
D00439  Nitrofurantoin (JAN/USP/INN)
D00453  Ofloxacin (JP18/USP/INN)
D00456  Ondansetron (JAN/USP/INN)
D00491  Paclitaxel (JAN/USP/INN)
D00512  Phenytoin (JP18/USP/INN)
D00521  Terfenadine (JAN/USAN/INN)
D00570  Colchicine (JP18/USP)
D00590  Sparfloxacin (JAN/USAN/INN)
D00767  Vecuronium bromide (JAN/USP/INN)
D00804  Ivermectin (JAN/USP/INN)
D01061  Irinotecan hydrochloride (USP)
D01264  Daunorubicin hydrochloride (JP18/USP)
D01275  Doxorubicin hydrochloride (JP18/USP)
D01421  Aminohippurate sodium (USP)
D01745  Domperidone (JP18/USAN/INN)
D01862  Pitavastatin calcium (JAN)
D02115  Methotrexate sodium
D02166  Mitoxantrone hydrochloride (JAN/USP)
D02214  Epirubicin hydrochloride (JP18/USP)
D02216  Ciprofloxacin hydrochloride (USP)
D02356  Verapamil (USAN/INN)
D03130  Bisantrene hydrochloride (USAN)
D03833  Indinavir (USAN)
D03899  Doxorubicin (USAN/INN)
D04931  Mercaptopurine (INN)
D05246  Olmesartan (USAN/INN)
D06050  Technetium Tc 99m tetrofosmin (USP)
D06074  Tenofovir (USAN)
D07448  Amitriptyline (INN)
D07538  Bosentan (INN)
D07626  Caspofungin (INN)
D07661  Cerivastatin (INN)
D07776  Daunorubicin (INN)
D07845  Diltiazem (INN)
D07866  Docetaxel (JAN/INN)
D07901  Epirubicin (INN)
D07907  Erlotinib (INN)
D07958  Fexofenadine (INN)
D07986  Folinic acid (BAN)
D07987  Folinic acid calcium salt pentahydrate
D08066  Imatinib (INN)
D08086  Irinotecan (INN)
D08108  Lapatinib (INN)
D08144  Loperamide (INN)
D08146  Losartan (INN)
D08224  Mitoxantrone (INN)
D08259  Nelfinavir (INN)
D08291  Ofloxacin hydrochloride
D08306  Oseltamivir (INN)
D08411  Prazosin (INN)
D08458  Quinidine (BAN)
D08492  Rosuvastatin (INN)
D08618  Topotecan (BAN)
D08675  Vinblastine (INN)
D08679  Vincristine (INN)
Reference
PMID:11826283
  Authors
Meier PJ, Stieger B
  Title
Bile salt transporters.
  Journal
Annu Rev Physiol 64:635-61 (2002)
DOI:10.1146/annurev.physiol.64.082201.100300
Reference
PMID:10728790
  Authors
Kullak-Ublick GA, Beuers U, Paumgartner G
  Title
Hepatobiliary transport.
  Journal
J Hepatol 32:3-18 (2000)
DOI:10.1016/S0168-8278(00)80411-0
Reference
PMID:18668439
  Authors
Kosters A, Karpen SJ
  Title
Bile acid transporters in health and disease.
  Journal
Xenobiotica 38:1043-71 (2008)
DOI:10.1080/00498250802040584
Reference
PMID:14999673
  Authors
Anwer MS
  Title
Cellular regulation of hepatic bile acid transport in health and cholestasis.
  Journal
Hepatology 39:581-90 (2004)
DOI:10.1002/hep.20090
Reference
PMID:17404808
  Authors
Alrefai WA, Gill RK
  Title
Bile acid transporters: structure, function, regulation and pathophysiological implications.
  Journal
Pharm Res 24:1803-23 (2007)
DOI:10.1007/s11095-007-9289-1
Reference
PMID:12663868
  Authors
Trauner M, Boyer JL
  Title
Bile salt transporters: molecular characterization, function, and regulation.
  Journal
Physiol Rev 83:633-71 (2003)
DOI:10.1152/physrev.00027.2002
Reference
PMID:20103563
  Authors
Klaassen CD, Aleksunes LM
  Title
Xenobiotic, bile acid, and cholesterol transporters: function and regulation.
  Journal
Pharmacol Rev 62:1-96 (2010)
DOI:10.1124/pr.109.002014
Reference
PMID:15758646
  Authors
Trauner M, Wagner M, Fickert P, Zollner G
  Title
Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis.
  Journal
J Clin Gastroenterol 39:S111-24 (2005)
DOI:10.1097/01.mcg.0000155551.37266.26
Reference
PMID:14659471
  Authors
Arrese M, Trauner M
  Title
Molecular aspects of bile formation and cholestasis.
  Journal
Trends Mol Med 9:558-64 (2003)
DOI:10.1016/j.molmed.2003.10.002
Reference
PMID:18837079
  Authors
Esteller A
  Title
Physiology of bile secretion.
  Journal
World J Gastroenterol 14:5641-9 (2008)
DOI:10.3748/wjg.14.5641
Reference
PMID:12483266
  Authors
Takikawa H
  Title
Hepatobiliary transport of bile acids and organic anions.
  Journal
J Hepatobiliary Pancreat Surg 9:443-7 (2002)
DOI:10.1007/s005340200055
Reference
PMID:11316487
  Authors
St-Pierre MV, Kullak-Ublick GA, Hagenbuch B, Meier PJ
  Title
Transport of bile acids in hepatic and non-hepatic tissues.
  Journal
J Exp Biol 204:1673-86 (2001)
Reference
PMID:18670431
  Authors
Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K
  Title
Targeting bile-acid signalling for metabolic diseases.
  Journal
Nat Rev Drug Discov 7:678-93 (2008)
DOI:10.1038/nrd2619
Reference
PMID:15975683
  Authors
Pauli-Magnus C, Stieger B, Meier Y, Kullak-Ublick GA, Meier PJ
  Title
Enterohepatic transport of bile salts and genetics of cholestasis.
  Journal
J Hepatol 43:342-57 (2005)
DOI:10.1016/j.jhep.2005.03.017
Reference
PMID:18081658
  Authors
Pellicoro A, Faber KN
  Title
Review article: The function and regulation of proteins involved in bile salt biosynthesis and transport.
  Journal
Aliment Pharmacol Ther 26 Suppl 2:149-60 (2007)
DOI:10.1111/j.1365-2036.2007.03522.x
Reference
PMID:19482594
  Authors
Jonker JW, Stedman CA, Liddle C, Downes M
  Title
Hepatobiliary ABC transporters: physiology, regulation and implications for disease.
  Journal
Front Biosci 14:4904-20 (2009)
DOI:10.2741/3576
Reference
PMID:19273385
  Authors
Modica S, Bellafante E, Moschetta A
  Title
Master regulation of bile acid and xenobiotic metabolism via the FXR, PXR and CAR trio.
  Journal
Front Biosci 14:4719-45 (2009)
DOI:10.2741/3563
Reference
PMID:16706681
  Authors
Cai SY, Boyer JL
  Title
FXR: a target for cholestatic syndromes?
  Journal
Expert Opin Ther Targets 10:409-21 (2006)
DOI:10.1517/14728222.10.3.409
Reference
PMID:19273238
  Authors
Ballatori N, Li N, Fang F, Boyer JL, Christian WV, Hammond CL
  Title
OST alpha-OST beta: a key membrane transporter of bile acids and conjugated steroids.
  Journal
Front Biosci 14:2829-44 (2009)
DOI:10.2741/3416
Reference
PMID:18377365
  Authors
Roma MG, Crocenzi FA, Sanchez Pozzi EA
  Title
Hepatocellular transport in acquired cholestasis: new insights into functional, regulatory and therapeutic aspects.
  Journal
Clin Sci (Lond) 114:567-88 (2008)
DOI:10.1042/CS20070227
Reference
PMID:18371245
  Authors
Arrese M, Macias RI, Briz O, Perez MJ, Marin JJ
  Title
Molecular pathogenesis of intrahepatic cholestasis of pregnancy.
  Journal
Expert Rev Mol Med 10:e9 (2008)
DOI:10.1017/S1462399408000628
Related
pathway
hsa00120  Primary bile acid biosynthesis
hsa04144  Endocytosis
hsa04530  Tight junction
hsa04975  Fat digestion and absorption
KO pathway
ko04976   

  All links  
Genome (1)   
   KEGG GENOME (1)   
Gene (90)   
   KEGG GENES (90)   
All databases (91)   

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