Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6GWW1P)

• DOT Name: NPC1-like intracellular cholesterol transporter 1 (NPC1L1)
• Synonyms: NPC1L1; Niemann-Pick C1-like protein 1
• Gene Name: NPC1L1
• UniProt ID: NPCL1_HUMAN
• PDB ID: 3QNT; 7DF8; 7DFW; 7DFZ; 7N4U; 7N4V; 7N4X
• Pfam ID: PF16414 ; PF02460 ; PF12349
• Sequence:
  MAEAGLRGWLLWALLLRLAQSEPYTTIHQPGYCAFYDECGKNPELSGSLMTLSNVSCLSN
  TPARKITGDHLILLQKICPRLYTGPNTQACCSAKQLVSLEASLSITKALLTRCPACSDNF
  VNLHCHNTCSPNQSLFINVTRVAQLGAGQLPAVVAYEAFYQHSFAEQSYDSCSRVRVPAA
  ATLAVGTMCGVYGSALCNAQRWLNFQGDTGNGLAPLDITFHLLEPGQAVGSGIQPLNEGV
  ARCNESQGDDVATCSCQDCAASCPAIARPQALDSTFYLGQMPGSLVLIIILCSVFAVVTI
  LLVGFRVAPARDKSKMVDPKKGTSLSDKLSFSTHTLLGQFFQGWGTWVASWPLTILVLSV
  IPVVALAAGLVFTELTTDPVELWSAPNSQARSEKAFHDQHFGPFFRTNQVILTAPNRSSY
  RYDSLLLGPKNFSGILDLDLLLELLELQERLRHLQVWSPEAQRNISLQDICYAPLNPDNT
  SLYDCCINSLLQYFQNNRTLLLLTANQTLMGQTSQVDWKDHFLYCANAPLTFKDGTALAL
  SCMADYGAPVFPFLAIGGYKGKDYSEAEALIMTFSLNNYPAGDPRLAQAKLWEEAFLEEM
  RAFQRRMAGMFQVTFMAERSLEDEINRTTAEDLPIFATSYIVIFLYISLALGSYSSWSRV
  MVDSKATLGLGGVAVVLGAVMAAMGFFSYLGIRSSLVILQVVPFLVLSVGADNIFIFVLE
  YQRLPRRPGEPREVHIGRALGRVAPSMLLCSLSEAICFFLGALTPMPAVRTFALTSGLAV
  ILDFLLQMSAFVALLSLDSKRQEASRLDVCCCVKPQELPPPGQGEGLLLGFFQKAYAPFL
  LHWITRGVVLLLFLALFGVSLYSMCHISVGLDQELALPKDSYLLDYFLFLNRYFEVGAPV
  YFVTTLGYNFSSEAGMNAICSSAGCNNFSFTQKIQYATEFPEQSYLAIPASSWVDDFIDW
  LTPSSCCRLYISGPNKDKFCPSTVNSLNCLKNCMSITMGSVRPSVEQFHKYLPWFLNDRP
  NIKCPKGGLAAYSTSVNLTSDGQVLDTVAILSPRLEYSGTISAHCNLYLLDSTSRFMAYH
  KPLKNSQDYTEALRAARELAANITADLRKVPGTDPAFEVFPYTITNVFYEQYLTILPEGL
  FMLSLCLVPTFAVSCLLLGLDLRSGLLNLLSIVMILVDTVGFMALWGISYNAVSLINLVS
  AVGMSVEFVSHITRSFAISTKPTWLERAKEATISMGSAVFAGVAMTNLPGILVLGLAKAQ
  LIQIFFFRLNLLITLLGLLHGLVFLPVILSYVGPDVNPALALEQKRAEEAVAAVMVASCP
  NHPSRVSTADNIYVNHSFEGSIKGAGAISNFLPNNGRQF
• Function: Plays a major role in cholesterol homeostasis. Critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Involved in plant sterol absorption, it transports sitosterol, although at lower rates than cholesterol. Is the direct molecular target of ezetimibe, a drug that inhibits cholesterol absorption and is approved for the treatment of hypercholesterolemia. May have a function in the transport of multiple lipids and their homeostasis, thereby influencing lipid metabolism regulation. May be involved in caveolin trafficking from the plasma membrane. In addition, acts as a negative regulator of NPC2 and down-regulates its expression and secretion by inhibiting its maturation and accelerating its degradation.
• Tissue Specificity: Widely expressed. Expressed in liver. Also expressed in small intestine, pancreas, kidney, lung, pancreas, spleen, heart, gall bladder, brain, testis, stomach and muscle.
• KEGG Pathway: Fat digestion and absorption (hsa04975)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ezetimibe	DM7A8TW	Approved	NPC1-like intracellular cholesterol transporter 1 (NPC1L1) decreases the response to substance of Ezetimibe.	[10]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of NPC1-like intracellular cholesterol transporter 1 (NPC1L1).	[1]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of NPC1-like intracellular cholesterol transporter 1 (NPC1L1).	[8]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NPC1-like intracellular cholesterol transporter 1 (NPC1L1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NPC1-like intracellular cholesterol transporter 1 (NPC1L1).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of NPC1-like intracellular cholesterol transporter 1 (NPC1L1).	[4]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of NPC1-like intracellular cholesterol transporter 1 (NPC1L1).	[5]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of NPC1-like intracellular cholesterol transporter 1 (NPC1L1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of NPC1-like intracellular cholesterol transporter 1 (NPC1L1).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NPC1-like intracellular cholesterol transporter 1 (NPC1L1).	[9]

References

• [1] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [2] Impairment of bile acid metabolism by perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in human HepaRG hepatoma cells. Arch Toxicol. 2020 May;94(5):1673-1686. doi: 10.1007/s00204-020-02732-3. Epub 2020 Apr 6.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [5] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [6] Effects of ezetimibe and/or simvastatin on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase gene expression: a randomized trial in healthy men. Atherosclerosis. 2008 May;198(1):198-207.
• [7] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [8] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [9] Bisphenol A promotes cholesterol absorption in Caco-2 cells by up-regulation of NPC1L1 expression. Lipids Health Dis. 2017 Jan 6;16(1):2. doi: 10.1186/s12944-016-0395-0.
• [10] Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe. Clin Genet. 2005 Feb;67(2):175-7. doi: 10.1111/j.1399-0004.2004.00388.x.