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Showing 611 - 620 of 49833 pathways
SMPDB ID Pathway Chemical Compounds Proteins


Pw000621 View Pathway
Drug Metabolism

Azathioprine Metabolism Pathway

Azathioprine is a purine antimetabolite prodrug that exerts cytotoxic effects via three mechanisms: via incorporation of thiodeoxyguanosine triphosphate into DNA and thioguanosine triphosphate into RNA, inhibition of de novo synthesis of purine nucleotides, and inhibition of Ras-related C3 botulinum toxin substrate 1, which induces apoptosis of activated T cells. Azathioprine is first converted _in vivo_ to mercaptopurine in the liver. Mercaptopurine then travels through the bloodstream and is transported into cells via nucleoside transporters. Mercaptopurine is converted to thioguanosince diphosphate through a series of metabolic reactions that produces the metabolic intermediates, thioinosine 5’-monophosphate, thioxanthine monophosphate, and thioguanosine monophosphate. Thioguanosine diphosphate is then converted via a thiodeoxyguanosine diphosphate intermediate to thiodeoxyguanosine triphosphate, which is incorporated into DNA. Thioguanosine diphosphate is also converted to thioguanosine triphosphate which is incorporated into RNA. The thioguanosine triphosphate metabolite also inhibits Ras-related C3 botulinum toxin substrate 1, a plasma membrane-associated small GTPase that regulates cellular processes, inducing apoptosis in activated T cells. Finally, de novo synthesis of purine nucleotides is inhibited by the methyl-thioinosine 5’-monophosphate metabolite, which inhibits amidophosphoribosyl-transferase, the enzyme that catalyzes one of the first steps in this pathway.


Pw000622 View Pathway
Drug Metabolism

Fluoxetine Metabolism Pathway

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.


Pw000623 View Pathway
Drug Metabolism

Thioguanine Metabolism Pathway

Thioguanine is a purine antimetabolite prodrug closely related to mercaptopurine and similarly inhibits purine metabolism. The thioguanine pathway is shown as a part of the mercaptopurine pathway. Thioguanine exerts cytotoxic effects via incorporation of thiodeoxyguanosine triphosphate into DNA and thioguanosine triphosphate into RNA and inhibition of Ras-related C3 botulinum toxin substrate 1, which induces apoptosis of activated T cells. Once in a cell, thioguanine is converted to thioguanosine monophosphate by hypoxanthine-guanine phosphoribosyltransferase. Thioguanosine monophosphate is then phosphorylated to thioguanosine diphosphate, which is converted via a thiodeoxyguanosine diphosphate intermediate to thiodeoxyguanosine triphosphate. Thiodeoxyguanosine triphosphate is incorporated into DNA causing cytotoxicity. Thioguanosine diphosphate is also converted to thioguanosine triphosphate which is incorporated into RNA. The thioguanosine triphosphate metabolite also inhibits Ras-related C3 botulinum toxin substrate 1, a plasma membrane-associated small GTPase that regulates cellular processes, inducing apoptosis in activated T cells.


Pw000624 View Pathway
Drug Metabolism

Sorafenib Metabolism Pathway

Sorafenib is a drug that belongs to the antineoplastics drug class, which is the drug class relating to the treatment of cancer, specifically renal, hepatic and thyroid cancers. This drug works by stopping cancerous tumour progress and stopping therapy replication pf potentially malignant cells. It does this by inhibiting protein synthesis, as we will explore in the pathway. Sorafenib is administered orally, in a tablet form taken twice daily without food. Once ingested, sorafenib finds itself in the endoplasmic reticulum membrane , where it inhibits cytochrome P450 2B6, cytochrome P450 2C8, cytochrome P450 2C9 and UDP-glucuronosyltransferase 1-1. Sorafenib is also catalyzed, with the help uridine diphosphate glucuronic acid and the enzyme UDP-glucuronosyltransferase 1-9 to sorafenib b-D-glucuronide with a by-product of uridine 5’-diphosphate. Sorafenib also undergoes a transformation without the use of catalytic enzymes and becomes sorafenib metabolite M4 and subsequently becomes sorafenib metabolite M5. In another reaction, sorafenib teams up with water and oxygen, using cytochrome P450 3A4 to create sorafenib N-oxide and hydrogen peroxide. Sorafenib N-oxide then undergoes two more reactions, one where it becomes sorafenib N-oxide glucuronide, and another where it becomes sorafenib metabolite M1. Sorafenib metabolite M1 is also attached to another reaction, as sorafenib creates sorafenib metabolite M3, sorafenib metabolite M1 is also created from this metabolite.


Pw000625 View Pathway
Drug Metabolism

Lamivudine Metabolism Pathway

Lamivudine (2'-deoxy-3'-thiacytidine, 3TC) is a pyrimidine analog reverse transcriptase enzyme inhibitor used to treat human immunodeficiency virus type I (HIV-1), HIV-2, and Hepatitis B. When metabolized to its active triphosphate form, it competes with deoxycytidine triphosphate for binding to reverse transcriptase, resulting in chain termination when incorporated into the viral DNA. Lamivudine may enter the cells by passive diffusion or by active transported via SLC22A1, SLC22A2, and SLC22A3. Intracellularly, it is phosphorylated to its active triphosphate from via deoxycytidine kinase (3TC to 3TC-monophosphate), followed by cytidine monophosphate/deoxycytidine monophosphate kinase (3TC-monophosphate to 3TC-diphosphate), then 3'-phosphoglycerate kinase or nucleoside diphosphate kinase (3TC-diphosphate to 3TC-triphosphate). Dephosphorylation can occur via phosphatases or salvage pathways. Lamivudine is actively transported out of cell by efflux transporters ABCB1, ABCC1, ABCC2, ABCC3, ABCC4 and ABCG2 and primarily excreted unchanged in the urine.


Pw000626 View Pathway
Drug Metabolism

Doxorubicin Metabolism Pathway

Doxorubicin is an anthracycline antibiotic used as a cancer chemotherapy drug. The major metabolic route of doxorubicin metabolism is two-electron reduction to doxorubicinol. A second route is one-electron reduction resulting in a doxorubicin-semiquinone, which can be undertaken by NADH dehydrogenases in the sarcoplasmic reticulum or mitochondrion, or nitric oxide synthases, NADPH dehydrogenase, or xanthine oxidase. Reactive oxygen species are formed when the semiquinone is re-oxidized back to doxorubicin. The reactive oxygen species are thought by some to be responsible for the drug's effects and cardiotoxicity, and can be deactivated by glutathione peroxidase, catalase, and superoxide dismutase. A third and minor metabolic route involves deglycosidation and results in the formation of doxirubicinol hydroxyaglycone. Approximately 50% of doxorubicin is eliminated unchanged from the body.


Pw000627 View Pathway
Drug Metabolism

Artemether Metabolism Pathway

Artemether is a semisynthetic derivative of artemisinin, a phytoconstituent that acts as a short-acting antimalarial agent and is used to treat uncomplicated Plasmodium falciparum malaria. Artemisinin derivatives kill parasites more rapidly than conventional antimalarial drugs, and are active against both the sexual and asexual stages of the parasite cycle. However due to their short half-life (and to prevent resistance development) artemisinin compounds are often combined with long-acting antimalarial drugs. Artemeter is administered orally and as an oil-based intramuscular injection. The antimalarial activity of artemether and other artemisinin derivatives is a result of the peroxide bridge found in the active metabolite dihydroartemisinin. Dihydroartemisinin is formed from the rapid demethylation of artmether via CYP3A4 and CYP3A5. It then undergoes glucuronidation catalyzed by the UDP-glucuronosyltransferases UGT1A9 and UGT2B7 into inactive metabolites that are eliminated in the bile.


Pw000628 View Pathway
Drug Metabolism

Mycophenolic Acid Metabolism Pathway

Mycophenolic Acid (MPA) is an immunosuppressive agent that acts as a noncompetitive, selective and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). It is available as a prodrug, Mycophenolate mofetil (MMF), which is a 2-morpholinoethyl ester with improved bioavailability. After absorption, MMF is hydrolyzed to MPA and N-(2-carboxymethyl)- morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine by the carboxylesterases CES-1 (in the liver only) and CES-2 (in the liver and intestine). The morpholine metabolites are excreted in the urine. MPA is glucuronidated by UDP glucuronosyl transferases (UGTs) UGT1A7, UGT1A8, UGT1A9 and UGT1A10 to MPA-7-O-glucuronide, which is excreted in the urine. Other metabolites of MPA include MPA-acyl glucoronide, which is formed by UGT2B7, and 6-O-desmethyl-MPA, which is formed by the CYP enzymes CYP3A4, CYP3A5 and CYP2C8. MPA enters hepatocytes by the organic anion transport proteins (OATPs) SLCO1B1 and SLCO1B3. MPA and its metabolites are excreted in the bile via the ABCC2, ABCG2, and ABCB1 proteins.


Pw000629 View Pathway
Drug Metabolism

Rosiglitazone Metabolism Pathway

Rosiglitazone is an anti-diabetic drug in the thiazolidinedione class of drugs. It is extensively metabolized in the liver by the cytochrome p450 enzymes CYP2C8 and CYP2C9 to para-hydroxy rosiglitazon, ortho-hydroxy rosiglitazone and N-desmethyl rosiglitazone. N-desmethyl rosiglitazone is the major metabolite and is further metabolized to N-desmethyl-p-hydroxyrosiglitazone, N-desmethyl glucuronide rosiglitazone and N-desmethyl-O-hydroxy rosiglitazone. Both para-hydroxy rosiglitazon and ortho-hydroxy rosiglitazone are excreted as sulfated or glucuronidated metabolites.


Pw000630 View Pathway

Aerobic Glycolysis (Warburg Effect)

The Warburg Effect refers to the phenomenon that occurs in most cancer cells where instead of generating energy with a low rate of glycolysis followed by oxidizing pyruvate via the Krebs cycle in the mitochondria, the pyruvate from a high rate of glycolysis undergoes lactic acid fermentation in the cytosol. As the Krebs cycle is an aerobic process, in normal cells lactate production is reserved for anaerobic conditions. However, cancer cells preferentially utilize glucose for lactate production via this “aerobic glycolysis”, even when oxygen is plentiful. The Warburg Effect is thought to be the result of mutations to oncogenes and tumour suppressor genes. It may be an adaptation to low-oxygen environments within tumours, the result of cancer genes shutting down the mitochondria, or a mechanism to aid cell proliferation via increased glycolysis. Proliferation may occur due to the accumulation of glycolytic intermediates (which lead to the production of nucleotides, amino acids, and fatty acids) after the final enzymatic reaction of glycolysis (phosphoenolpyruvate into pyruvate) is slowed down. This reaction produces lactic acid which leads to a low pH microenvironment and the lactate shuttle can activate angiogenesis factors from surrounding cells. The Warburg Effect involves numerous pathways, including growth factor stimulation, transcriptional activation, and glycolysis promotion.
Showing 611 - 620 of 49833 pathways