Molecule Information

General Information of the Molecule (ID: Mol01859)

• Name: Cytochrome P450 family 1 subfamily A member 1 (CYP1A1) ,Homo sapiens
• Synonyms: CYP1A1
• Molecule Type: Protein
• Gene Name: CYP1A1
• Gene ID: 1543
• Location: chr15:74,719,542-74,725,536[-]
• Sequence:
  MLFPISMSATEFLLASVIFCLVFWVIRASRPQVPKGLKNPPGPWGWPLIGHMLTLGKNPH
  LALSRMSQQYGDVLQIRIGSTPVVVLSGLDTIRQALVRQGDDFKGRPDLYTFTLISNGQS
  MSFSPDSGPVWAARRRLAQNGLKSFSIASDPASSTSCYLEEHVSKEAEVLISTLQELMAG
  PGHFNPYRYVVVSVTNVICAICFGRRYDHNHQELLSLVNLNNNFGEVVGSGNPADFIPIL
  RYLPNPSLNAFKDLNEKFYSFMQKMVKEHYKTFEKGHIRDITDSLIEHCQEKQLDENANV
  QLSDEKIINIVLDLFGAGFDTVTTAISWSLMYLVMNPRVQRKIQEELDTVIGRSRRPRLS
  DRSHLPYMEAFILETFRHSSFVPFTIPHSTTRDTSLKGFYIPKGRCVFVNQWQINHDQKL
  WVNPSEFLPERFLTPDGAIDKVLSEKVIIFGMGKRKCIGETIARWEVFLFLAILLQRVEF
  SVPLGVKVDMTPIYGLTMKHACCEHFQMQLRS
• Function: A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds. Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C15-alpha and C16-alpha positions. Displays different regioselectivities for polyunsaturated fatty acids (PUFA) hydroxylation. Catalyzes the epoxidation of double bonds of certain PUFA. Converts arachidonic acid toward epoxyeicosatrienoic acid (EET) regioisomers, 8,9-, 11,12-, and 14,15-EET, that function as lipid mediators in the vascular system. Displays an absolute stereoselectivity in the epoxidation of eicosapentaenoic acid (EPA) producing the 17(R),18(S) enantiomer. May play an important role in all-trans retinoic acid biosynthesis in extrahepatic tissues. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid. May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent).
• Uniprot ID: CP1A1_HUMAN
• Ensembl ID: ENSG00000140465
• HGNC ID: HGNC:2595

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Clopidogrel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Acute Ischemic Stroke [1]

• Resistant Disease: Acute Ischemic Stroke [ICD-11: 8B11.0]
• Resistant Drug: Clopidogrel
• Molecule Alteration: Missense mutation; CYP3A5 (rs776746) GG + AG and CYP2C19*2 (rs4244285) AA + AG genotypes
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Matrix-assisted laser desorption/ionization time of flight mass spectrometry assay
• Experiment for Drug Resistance: Platelet aggregation test assay
• Mechanism Description: The estimated risk of clopidogrel resistance was significantly higher in patients with CYP3A5 (rs776746) GG and CYP2C19*2 (rs4244285) AA, as compared to patients harboring CYP3A5 (rs776746) AA and CYP2C19*2 (rs4244285) GG. These data suggest that these two CYP genetic variants together significantly contributed to clopidogrel resistance. The relative risk conferred by the combinations of CYP3A5 GG and CYP2C19*2 AA was considered as a high-risk variable, with assigned as one, and other combinations of CYP3A5 and CYP2C19*2 as a low-risk variable, with assigned as zero.

Ivermectin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Pediculosis [2]

• Resistant Disease: Pediculosis [ICD-11: 1G00.0]
• Resistant Drug: Ivermectin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pediculus humanus; 121225
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: Phylogenetic relatedness of P450 and ABC transporter genes over-transcribed following ivermectin exposure.Knockdown of CYP9AG2 P450 and ABCC4 transporter gene expression by RNA interference and subsequent increase in the sensitivity of lice to ivermectin.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 08

Cerebral ischaemic stroke [ICD-11: 8B11]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Whole blood
• The Specified Disease: Cardioembolic Stroke
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.24E-02; Fold-change: 2.60E-02; Z-score: 1.93E-01
• The Studied Tissue: Peripheral blood
• The Specified Disease: Ischemic stroke
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.00E-01; Fold-change: 1.96E-02; Z-score: 1.29E-01

References

• Ref 1: Association of Cytochrome P450 Genetic Variants with Clopidogrel Resistance and Outcomes in Acute Ischemic Stroke .J Atheroscler Thromb. 2016 Oct 1;23(10):1188-1200. doi: 10.5551/jat.33290. Epub 2016 Mar 8. 10.5551/jat.33290
• Ref 2: Ivermectin: From theory to clinical application .Int J Antimicrob Agents. 2019 Aug;54(2):134-142. doi: 10.1016/j.ijantimicag.2019.05.003. Epub 2019 May 7. 10.1016/j.ijantimicag.2019.05.003