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Pathway Description
Fluoxetine Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2013-08-22
Last Updated: 2019-08-16
Fluoxetine is a selective serotonin reuptake inhibitor that exerts antidepressive effects by selectively inhibiting serotonin reuptake in the brain. It does so by competing for the same binding site as serotonin on the the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of serotonin in the synaptic cleft and reverses the state of low concentration seen in depression. Higher concentration of serotonin has also been shown to have long-term neuromodulatory effects. Binding of serotonin to certain serotonin receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression.
References
Fluoxetine Pathway References
Prozac. (2009). e-CPS (online version of Compendium of Pharmaceuticals and Specialties). Retrieved December 23, 2009.
Shelton RC: The dual-action hypothesis: does pharmacology matter? J Clin Psychiatry. 2004;65 Suppl 17:5-10.
Pubmed: 15600376
Lesch KP, Wolozin BL, Estler HC, Murphy DL, Riederer P: Isolation of a cDNA encoding the human brain serotonin transporter. J Neural Transm Gen Sect. 1993;91(1):67-72.
Pubmed: 8452685
Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD: Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2542-6. doi: 10.1073/pnas.90.6.2542.
Pubmed: 7681602
Lesch KP, Wolozin BL, Murphy DL, Reiderer P: Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. J Neurochem. 1993 Jun;60(6):2319-22. doi: 10.1111/j.1471-4159.1993.tb03522.x.
Pubmed: 7684072
Kimura S, Umeno M, Skoda RC, Meyer UA, Gonzalez FJ: The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet. 1989 Dec;45(6):889-904.
Pubmed: 2574001
Gaedigk A, Bhathena A, Ndjountche L, Pearce RE, Abdel-Rahman SM, Alander SW, Bradford LD, Rogan PK, Leeder JS: Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans. Pharmacogenomics J. 2005;5(3):173-82. doi: 10.1038/sj.tpj.6500305.
Pubmed: 15768052
Sridar C, Snider NT, Hollenberg PF: Anandamide oxidation by wild-type and polymorphically expressed CYP2B6 and CYP2D6. Drug Metab Dispos. 2011 May;39(5):782-8. doi: 10.1124/dmd.110.036707. Epub 2011 Feb 2.
Pubmed: 21289075
Schuetz JD, Schuetz EG, Thottassery JV, Guzelian PS, Strom S, Sun D: Identification of a novel dexamethasone responsive enhancer in the human CYP3A5 gene and its activation in human and rat liver cells. Mol Pharmacol. 1996 Jan;49(1):63-72.
Pubmed: 8569713
Jounaidi Y, Guzelian PS, Maurel P, Vilarem MJ: Sequence of the 5'-flanking region of CYP3A5: comparative analysis with CYP3A4 and CYP3A7. Biochem Biophys Res Commun. 1994 Dec 30;205(3):1741-7. doi: 10.1006/bbrc.1994.2870.
Pubmed: 7811260
Aoyama T, Yamano S, Waxman DJ, Lapenson DP, Meyer UA, Fischer V, Tyndale R, Inaba T, Kalow W, Gelboin HV, et al.: Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem. 1989 Jun 25;264(18):10388-95.
Pubmed: 2732228
Hsieh KP, Lin YY, Cheng CL, Lai ML, Lin MS, Siest JP, Huang JD: Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos. 2001 Mar;29(3):268-73.
Pubmed: 11181494
Molowa DT, Schuetz EG, Wrighton SA, Watkins PB, Kremers P, Mendez-Picon G, Parker GA, Guzelian PS: Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5311-5. doi: 10.1073/pnas.83.14.5311.
Pubmed: 3460094
Gonzalez FJ, Schmid BJ, Umeno M, Mcbride OW, Hardwick JP, Meyer UA, Gelboin HV, Idle JR: Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA. 1988 Mar;7(2):79-86. doi: 10.1089/dna.1988.7.79.
Pubmed: 3267210
Meehan RR, Gosden JR, Rout D, Hastie ND, Friedberg T, Adesnik M, Buckland R, van Heyningen V, Fletcher J, Spurr NK, et al.: Human cytochrome P-450 PB-1: a multigene family involved in mephenytoin and steroid oxidations that maps to chromosome 10. Am J Hum Genet. 1988 Jan;42(1):26-37.
Pubmed: 2827463
Kimura S, Pastewka J, Gelboin HV, Gonzalez FJ: cDNA and amino acid sequences of two members of the human P450IIC gene subfamily. Nucleic Acids Res. 1987 Dec 10;15(23):10053-4. doi: 10.1093/nar/15.23.10053.
Pubmed: 3697070
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Miyazawa M, Shindo M, Shimada T: Metabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes. Drug Metab Dispos. 2002 May;30(5):602-7. doi: 10.1124/dmd.30.5.602.
Pubmed: 11950794
Ibeanu GC, Goldstein JA, Meyer U, Benhamou S, Bouchardy C, Dayer P, Ghanayem BI, Blaisdell J: Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin. J Pharmacol Exp Ther. 1998 Sep;286(3):1490-5.
Pubmed: 9732415
Ibeanu GC, Blaisdell J, Ghanayem BI, Beyeler C, Benhamou S, Bouchardy C, Wilkinson GR, Dayer P, Daly AK, Goldstein JA: An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians. Pharmacogenetics. 1998 Apr;8(2):129-35.
Pubmed: 10022751
Denier C, Ducros A, Durr A, Eymard B, Chassande B, Tournier-Lasserve E: Missense CACNA1A mutation causing episodic ataxia type 2. Arch Neurol. 2001 Feb;58(2):292-5. doi: 10.1001/archneur.58.2.292.
Pubmed: 11176968
Hans M, Urrutia A, Deal C, Brust PF, Stauderman K, Ellis SB, Harpold MM, Johnson EC, Williams ME: Structural elements in domain IV that influence biophysical and pharmacological properties of human alpha1A-containing high-voltage-activated calcium channels. Biophys J. 1999 Mar;76(3):1384-400. doi: 10.1016/S0006-3495(99)77300-5.
Pubmed: 10049321
Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR: Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996 Nov 1;87(3):543-52. doi: 10.1016/s0092-8674(00)81373-2.
Pubmed: 8898206
Powers PA, Liu S, Hogan K, Gregg RG: Skeletal muscle and brain isoforms of a beta-subunit of human voltage-dependent calcium channels are encoded by a single gene. J Biol Chem. 1992 Nov 15;267(32):22967-72.
Pubmed: 1385409
Williams ME, Feldman DH, McCue AF, Brenner R, Velicelebi G, Ellis SB, Harpold MM: Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron. 1992 Jan;8(1):71-84. doi: 10.1016/0896-6273(92)90109-q.
Pubmed: 1309651
Collin T, Wang JJ, Nargeot J, Schwartz A: Molecular cloning of three isoforms of the L-type voltage-dependent calcium channel beta subunit from normal human heart. Circ Res. 1993 Jun;72(6):1337-44. doi: 10.1161/01.res.72.6.1337.
Pubmed: 7916667
Neuron Function References
Lovinger DM: Communication networks in the brain: neurons, receptors, neurotransmitters, and alcohol. Alcohol Res Health. 2008;31(3):196-214.
Pubmed: 23584863
Kress GJ, Mennerick S: Action potential initiation and propagation: upstream influences on neurotransmission. Neuroscience. 2009 Jan 12;158(1):211-22. doi: 10.1016/j.neuroscience.2008.03.021. Epub 2008 Mar 19.
Pubmed: 18472347
Platkiewicz J, Brette R: A threshold equation for action potential initiation. PLoS Comput Biol. 2010 Jul 8;6(7):e1000850. doi: 10.1371/journal.pcbi.1000850.
Pubmed: 20628619
Lesch KP, Wolozin BL, Estler HC, Murphy DL, Riederer P: Isolation of a cDNA encoding the human brain serotonin transporter. J Neural Transm Gen Sect. 1993;91(1):67-72.
Pubmed: 8452685
Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD: Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2542-6. doi: 10.1073/pnas.90.6.2542.
Pubmed: 7681602
Lesch KP, Wolozin BL, Murphy DL, Reiderer P: Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. J Neurochem. 1993 Jun;60(6):2319-22. doi: 10.1111/j.1471-4159.1993.tb03522.x.
Pubmed: 7684072
Kimura S, Umeno M, Skoda RC, Meyer UA, Gonzalez FJ: The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet. 1989 Dec;45(6):889-904.
Pubmed: 2574001
Gaedigk A, Bhathena A, Ndjountche L, Pearce RE, Abdel-Rahman SM, Alander SW, Bradford LD, Rogan PK, Leeder JS: Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans. Pharmacogenomics J. 2005;5(3):173-82. doi: 10.1038/sj.tpj.6500305.
Pubmed: 15768052
Sridar C, Snider NT, Hollenberg PF: Anandamide oxidation by wild-type and polymorphically expressed CYP2B6 and CYP2D6. Drug Metab Dispos. 2011 May;39(5):782-8. doi: 10.1124/dmd.110.036707. Epub 2011 Feb 2.
Pubmed: 21289075
Schuetz JD, Schuetz EG, Thottassery JV, Guzelian PS, Strom S, Sun D: Identification of a novel dexamethasone responsive enhancer in the human CYP3A5 gene and its activation in human and rat liver cells. Mol Pharmacol. 1996 Jan;49(1):63-72.
Pubmed: 8569713
Jounaidi Y, Guzelian PS, Maurel P, Vilarem MJ: Sequence of the 5'-flanking region of CYP3A5: comparative analysis with CYP3A4 and CYP3A7. Biochem Biophys Res Commun. 1994 Dec 30;205(3):1741-7. doi: 10.1006/bbrc.1994.2870.
Pubmed: 7811260
Aoyama T, Yamano S, Waxman DJ, Lapenson DP, Meyer UA, Fischer V, Tyndale R, Inaba T, Kalow W, Gelboin HV, et al.: Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem. 1989 Jun 25;264(18):10388-95.
Pubmed: 2732228
Hsieh KP, Lin YY, Cheng CL, Lai ML, Lin MS, Siest JP, Huang JD: Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos. 2001 Mar;29(3):268-73.
Pubmed: 11181494
Molowa DT, Schuetz EG, Wrighton SA, Watkins PB, Kremers P, Mendez-Picon G, Parker GA, Guzelian PS: Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5311-5. doi: 10.1073/pnas.83.14.5311.
Pubmed: 3460094
Gonzalez FJ, Schmid BJ, Umeno M, Mcbride OW, Hardwick JP, Meyer UA, Gelboin HV, Idle JR: Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA. 1988 Mar;7(2):79-86. doi: 10.1089/dna.1988.7.79.
Pubmed: 3267210
Meehan RR, Gosden JR, Rout D, Hastie ND, Friedberg T, Adesnik M, Buckland R, van Heyningen V, Fletcher J, Spurr NK, et al.: Human cytochrome P-450 PB-1: a multigene family involved in mephenytoin and steroid oxidations that maps to chromosome 10. Am J Hum Genet. 1988 Jan;42(1):26-37.
Pubmed: 2827463
Kimura S, Pastewka J, Gelboin HV, Gonzalez FJ: cDNA and amino acid sequences of two members of the human P450IIC gene subfamily. Nucleic Acids Res. 1987 Dec 10;15(23):10053-4. doi: 10.1093/nar/15.23.10053.
Pubmed: 3697070
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Miyazawa M, Shindo M, Shimada T: Metabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes. Drug Metab Dispos. 2002 May;30(5):602-7. doi: 10.1124/dmd.30.5.602.
Pubmed: 11950794
Ibeanu GC, Goldstein JA, Meyer U, Benhamou S, Bouchardy C, Dayer P, Ghanayem BI, Blaisdell J: Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin. J Pharmacol Exp Ther. 1998 Sep;286(3):1490-5.
Pubmed: 9732415
Ibeanu GC, Blaisdell J, Ghanayem BI, Beyeler C, Benhamou S, Bouchardy C, Wilkinson GR, Dayer P, Daly AK, Goldstein JA: An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians. Pharmacogenetics. 1998 Apr;8(2):129-35.
Pubmed: 10022751
Denier C, Ducros A, Durr A, Eymard B, Chassande B, Tournier-Lasserve E: Missense CACNA1A mutation causing episodic ataxia type 2. Arch Neurol. 2001 Feb;58(2):292-5. doi: 10.1001/archneur.58.2.292.
Pubmed: 11176968
Hans M, Urrutia A, Deal C, Brust PF, Stauderman K, Ellis SB, Harpold MM, Johnson EC, Williams ME: Structural elements in domain IV that influence biophysical and pharmacological properties of human alpha1A-containing high-voltage-activated calcium channels. Biophys J. 1999 Mar;76(3):1384-400. doi: 10.1016/S0006-3495(99)77300-5.
Pubmed: 10049321
Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR: Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996 Nov 1;87(3):543-52. doi: 10.1016/s0092-8674(00)81373-2.
Pubmed: 8898206
Powers PA, Liu S, Hogan K, Gregg RG: Skeletal muscle and brain isoforms of a beta-subunit of human voltage-dependent calcium channels are encoded by a single gene. J Biol Chem. 1992 Nov 15;267(32):22967-72.
Pubmed: 1385409
Williams ME, Feldman DH, McCue AF, Brenner R, Velicelebi G, Ellis SB, Harpold MM: Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron. 1992 Jan;8(1):71-84. doi: 10.1016/0896-6273(92)90109-q.
Pubmed: 1309651
Collin T, Wang JJ, Nargeot J, Schwartz A: Molecular cloning of three isoforms of the L-type voltage-dependent calcium channel beta subunit from normal human heart. Circ Res. 1993 Jun;72(6):1337-44. doi: 10.1161/01.res.72.6.1337.
Pubmed: 7916667
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