Details of Drug Off-Target (DOT)

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

• DOT Name: Cytochrome P450 3A5 (CYP3A5)
• Synonyms: EC 1.14.14.1; CYPIIIA5; Cytochrome P450-PCN3
• Gene Name: CYP3A5
• UniProt ID: CP3A5_HUMAN
• PDB ID: 5VEU
• EC Number: 1.14.14.1
• Pfam ID: PF00067
• Sequence:
  MDLIPNLAVETWLLLAVSLVLLYLYGTRTHGLFKRLGIPGPTPLPLLGNVLSYRQGLWKF
  DTECYKKYGKMWGTYEGQLPVLAITDPDVIRTVLVKECYSVFTNRRSLGPVGFMKSAISL
  AEDEEWKRIRSLLSPTFTSGKLKEMFPIIAQYGDVLVRNLRREAEKGKPVTLKDIFGAYS
  MDVITGTSFGVNIDSLNNPQDPFVESTKKFLKFGFLDPLFLSIILFPFLTPVFEALNVSL
  FPKDTINFLSKSVNRMKKSRLNDKQKHRLDFLQLMIDSQNSKETESHKALSDLELAAQSI
  IFIFAGYETTSSVLSFTLYELATHPDVQQKLQKEIDAVLPNKAPPTYDAVVQMEYLDMVV
  NETLRLFPVAIRLERTCKKDVEINGVFIPKGSMVVIPTYALHHDPKYWTEPEEFRPERFS
  KKKDSIDPYIYTPFGTGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLDTQG
  LLQPEKPIVLKVDSRDGTLSGE
• Function: A cytochrome P450 monooxygenase involved in the metabolism of 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 catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2. Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione. Catalyzes the oxidative conversion of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA). Further metabolizes all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance. Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Retinol metabolism (hsa00830)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Drug metabolism - cytochrome P450 (hsa00982)
  Metabolic pathways (hsa01100)
  Chemical carcinogenesis - D. adducts (hsa05204)
• Reactome Pathway:
  Aflatoxin activation and detoxification (R-HSA-5423646)
  Xenobiotics (R-HSA-211981)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 18 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Troglitazone	DM3VFPD	Approved	Cytochrome P450 3A5 (CYP3A5) increases the metabolism of Troglitazone.	[41]
Clozapine	DMFC71L	Approved	Cytochrome P450 3A5 (CYP3A5) increases the metabolism of Clozapine.	[43]
Amodiaquine	DME4RA8	Approved	Cytochrome P450 3A5 (CYP3A5) increases the metabolism of Amodiaquine.	[53]
Thiotepa	DMIZKOP	Approved	Cytochrome P450 3A5 (CYP3A5) affects the export of Thiotepa.	[58]
Eplerenone	DMF0NQR	Approved	Cytochrome P450 3A5 (CYP3A5) increases the abundance of Eplerenone.	[62]
Erdafitinib	DMI782S	Approved	Cytochrome P450 3A5 (CYP3A5) increases the metabolism of Erdafitinib.	[63]
CQA 206-291	DM60TVK	Phase 3	Cytochrome P450 3A5 (CYP3A5) increases the metabolism of CQA 206-291.	[66]
Tanespimycin	DMNLQHK	Phase 2	Cytochrome P450 3A5 (CYP3A5) affects the metabolism of Tanespimycin.	[67]
(Z)-endoxifen	DMGDOS2	Phase 2	Cytochrome P450 3A5 (CYP3A5) increases the metabolism of (Z)-endoxifen.	[68]
Icaritin	DMGHQ37	Phase 2	Cytochrome P450 3A5 (CYP3A5) increases the metabolism of Icaritin.	[69]
Carfentanil	DM7ADGX	Phase 2	Cytochrome P450 3A5 (CYP3A5) increases the metabolism of Carfentanil.	[70]
Bisphenol A	DM2ZLD7	Investigative	Cytochrome P450 3A5 (CYP3A5) increases the metabolism of Bisphenol A.	[74]
geraniol	DMS3CBD	Investigative	Cytochrome P450 3A5 (CYP3A5) increases the metabolism of geraniol.	[75]
Phencyclidine	DMQBEYX	Investigative	Cytochrome P450 3A5 (CYP3A5) affects the metabolism of Phencyclidine.	[76]
1,4-Naphthoquinone	DMTCMH7	Investigative	Cytochrome P450 3A5 (CYP3A5) increases the abundance of 1,4-Naphthoquinone.	[77]
Fenthion	DMKEG49	Investigative	Cytochrome P450 3A5 (CYP3A5) affects the metabolism of Fenthion.	[78]
aconitine	DMFOZ60	Investigative	Cytochrome P450 3A5 (CYP3A5) increases the metabolism of aconitine.	[79]
TEPA (possesses cytotoxic activity)	DMROS5K	Investigative	Cytochrome P450 3A5 (CYP3A5) affects the export of TEPA (possesses cytotoxic activity).	[58]

This DOT Affected the Biotransformations of 23 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Cytochrome P450 3A5 (CYP3A5) decreases the methylation of Etoposide.	[42]
Ethinyl estradiol	DMODJ40	Approved	Cytochrome P450 3A5 (CYP3A5) increases the hydroxylation of Ethinyl estradiol.	[44]
Ifosfamide	DMCT3I8	Approved	Cytochrome P450 3A5 (CYP3A5) decreases the ethylation of Ifosfamide.	[47]
Imatinib	DM7RJXL	Approved	Cytochrome P450 3A5 (CYP3A5) decreases the methylation of Imatinib.	[48]
Cholecalciferol	DMGU74E	Approved	Cytochrome P450 3A5 (CYP3A5) increases the hydroxylation of Cholecalciferol.	[49]
Tacrolimus	DMZ7XNQ	Approved	Cytochrome P450 3A5 (CYP3A5) decreases the methylation of Tacrolimus.	[51]
Prasterone	DM67VKL	Approved	Cytochrome P450 3A5 (CYP3A5) increases the hydroxylation of Prasterone.	[52]
Erythromycin	DM4K7GQ	Approved	Cytochrome P450 3A5 (CYP3A5) decreases the methylation of Erythromycin.	[54]
Lidocaine	DML4ZOT	Approved	Cytochrome P450 3A5 (CYP3A5) decreases the methylation of Lidocaine.	[54]
Teniposide	DMLW57T	Approved	Cytochrome P450 3A5 (CYP3A5) decreases the methylation of Teniposide.	[42]
Dextromethorphan	DMUDJZM	Approved	Cytochrome P450 3A5 (CYP3A5) decreases the methylation of Dextromethorphan.	[54]
Flunitrazepam	DMGR5Z3	Approved	Cytochrome P450 3A5 (CYP3A5) increases the hydroxylation of Flunitrazepam.	[54]
Midazolam	DMXOELT	Approved	Cytochrome P450 3A5 (CYP3A5) increases the hydroxylation of Midazolam.	[54]
Alprazolam	DMC7XDN	Approved	Cytochrome P450 3A5 (CYP3A5) increases the hydroxylation of Alprazolam.	[60]
Buspirone	DMBS632	Approved	Cytochrome P450 3A5 (CYP3A5) increases the oxidation of Buspirone.	[61]
Rivaroxaban	DMQMBZ1	Approved	Cytochrome P450 3A5 (CYP3A5) increases the hydroxylation of Rivaroxaban.	[63]
N-DESMETHYLCLOZAPINE	DMVIRN3	Phase 2	Cytochrome P450 3A5 (CYP3A5) increases the chemical synthesis of N-DESMETHYLCLOZAPINE.	[43]
Tetrandrine	DMAOJBX	Phase 1	Cytochrome P450 3A5 (CYP3A5) increases the glutathionylation of Tetrandrine.	[71]
EMODIN	DMAEDQG	Terminated	Cytochrome P450 3A5 (CYP3A5) increases the hydroxylation of EMODIN.	[72]
HELENALIN	DMMCI4H	Terminated	Cytochrome P450 3A5 (CYP3A5) increases the oxidation of HELENALIN.	[73]
	DM9CEI5		Cytochrome P450 3A5 (CYP3A5) increases the oxidation of .	[64]
eucalyptol	DME5CK3	Investigative	Cytochrome P450 3A5 (CYP3A5) increases the hydroxylation of eucalyptol.	[80]
Alpha-Hydroxy-Midazolam	DMAQBKX	Investigative	Cytochrome P450 3A5 (CYP3A5) increases the chemical synthesis of Alpha-Hydroxy-Midazolam.	[81]

This DOT Affected the Drug Response of 11 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Simvastatin	DM30SGU	Approved	Cytochrome P450 3A5 (CYP3A5) affects the response to substance of Simvastatin.	[45]
Cyclophosphamide	DM4O2Z7	Approved	Cytochrome P450 3A5 (CYP3A5) affects the response to substance of Cyclophosphamide.	[46]
Warfarin	DMJYCVW	Approved	Cytochrome P450 3A5 (CYP3A5) affects the response to substance of Warfarin.	[50]
Clopidogrel	DMOL54H	Approved	Cytochrome P450 3A5 (CYP3A5) affects the response to substance of Clopidogrel.	[55]
Dronedarone	DMA8FS5	Approved	Cytochrome P450 3A5 (CYP3A5) decreases the response to substance of Dronedarone.	[56]
Amlodipine	DMBDAZV	Approved	Cytochrome P450 3A5 (CYP3A5) affects the response to substance of Amlodipine.	[57]
Valsartan	DMREUQ6	Approved	Cytochrome P450 3A5 (CYP3A5) affects the response to substance of Valsartan.	[57]
Brilinta	DMBR01X	Approved	Cytochrome P450 3A5 (CYP3A5) increases the Acute coronary syndrome ADR of Brilinta.	[59]
TOCOTRIENOL	DM1UE67	Approved	Cytochrome P450 3A5 (CYP3A5) affects the response to substance of TOCOTRIENOL.	[64]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Cytochrome P450 3A5 (CYP3A5) decreases the response to substance of Chlorpromazine.	[65]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Cytochrome P450 3A5 (CYP3A5) decreases the response to substance of Amiodarone.	[65]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cytochrome P450 3A5 (CYP3A5).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytochrome P450 3A5 (CYP3A5).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome P450 3A5 (CYP3A5).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cytochrome P450 3A5 (CYP3A5).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cytochrome P450 3A5 (CYP3A5).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cytochrome P450 3A5 (CYP3A5).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cytochrome P450 3A5 (CYP3A5).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Cytochrome P450 3A5 (CYP3A5).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Cytochrome P450 3A5 (CYP3A5).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Cytochrome P450 3A5 (CYP3A5).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cytochrome P450 3A5 (CYP3A5).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Cytochrome P450 3A5 (CYP3A5).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Cytochrome P450 3A5 (CYP3A5).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Cytochrome P450 3A5 (CYP3A5).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the activity of Cytochrome P450 3A5 (CYP3A5).	[14]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Cytochrome P450 3A5 (CYP3A5).	[15]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Cytochrome P450 3A5 (CYP3A5).	[16]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Cytochrome P450 3A5 (CYP3A5).	[17]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Cytochrome P450 3A5 (CYP3A5).	[18]
Thalidomide	DM70BU5	Approved	Thalidomide increases the expression of Cytochrome P450 3A5 (CYP3A5).	[19]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Cytochrome P450 3A5 (CYP3A5).	[9]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the expression of Cytochrome P450 3A5 (CYP3A5).	[20]
Ritonavir	DMU764S	Approved	Ritonavir decreases the activity of Cytochrome P450 3A5 (CYP3A5).	[21]
Omeprazole	DM471KJ	Approved	Omeprazole increases the expression of Cytochrome P450 3A5 (CYP3A5).	[22]
Clotrimazole	DMMFCIH	Approved	Clotrimazole increases the expression of Cytochrome P450 3A5 (CYP3A5).	[23]
Nelfinavir mesylate	DMFX6G8	Approved	Nelfinavir mesylate decreases the activity of Cytochrome P450 3A5 (CYP3A5).	[21]
Budesonide	DMJIBAW	Approved	Budesonide increases the expression of Cytochrome P450 3A5 (CYP3A5).	[24]
Reserpine	DM6VM38	Approved	Reserpine increases the expression of Cytochrome P450 3A5 (CYP3A5).	[23]
Fluticasone propionate	DMRWLB2	Approved	Fluticasone propionate increases the expression of Cytochrome P450 3A5 (CYP3A5).	[25]
Dabrafenib	DMX6OE3	Approved	Dabrafenib decreases the activity of Cytochrome P450 3A5 (CYP3A5).	[27]
Flunisolide	DMZSWQC	Approved	Flunisolide increases the expression of Cytochrome P450 3A5 (CYP3A5).	[25]
Troleandomycin	DMUZNIG	Approved	Troleandomycin decreases the activity of Cytochrome P450 3A5 (CYP3A5).	[28]
Beclomethasone dipropionate	DM5NW1E	Phase 4	Beclomethasone dipropionate increases the expression of Cytochrome P450 3A5 (CYP3A5).	[24]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil decreases the activity of Cytochrome P450 3A5 (CYP3A5).	[29]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Cytochrome P450 3A5 (CYP3A5).	[11]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the activity of Cytochrome P450 3A5 (CYP3A5).	[30]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Cytochrome P450 3A5 (CYP3A5).	[31]
PD-0325901	DM27D4J	Phase 2	PD-0325901 increases the expression of Cytochrome P450 3A5 (CYP3A5).	[32]
Impoyz	DMB1N6P	Phase 2	Impoyz increases the expression of Cytochrome P450 3A5 (CYP3A5).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytochrome P450 3A5 (CYP3A5).	[34]
Droloxifene	DM9JPUD	Discontinued in Phase 2	Droloxifene decreases the activity of Cytochrome P450 3A5 (CYP3A5).	[30]
Deguelin	DMXT7WG	Investigative	Deguelin affects the expression of Cytochrome P450 3A5 (CYP3A5).	[35]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Cytochrome P450 3A5 (CYP3A5).	[36]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Cytochrome P450 3A5 (CYP3A5).	[37]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of Cytochrome P450 3A5 (CYP3A5).	[38]
U0126	DM31OGF	Investigative	U0126 increases the expression of Cytochrome P450 3A5 (CYP3A5).	[32]
Hyperforin	DM2L3PE	Investigative	Hyperforin increases the expression of Cytochrome P450 3A5 (CYP3A5).	[39]
CI-1040	DMF3DZX	Investigative	CI-1040 increases the expression of Cytochrome P450 3A5 (CYP3A5).	[32]
TAMARIXETIN	DM0EP51	Investigative	TAMARIXETIN increases the expression of Cytochrome P450 3A5 (CYP3A5).	[40]

1 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Nortriptyline	DM4KDYJ	Approved	Nortriptyline increases the metabolism of Cytochrome P450 3A5 (CYP3A5).	[26]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] Triclosan treatment decreased the antitumor effect of sorafenib on hepatocellular carcinoma cells. Onco Targets Ther. 2018 May 18;11:2945-2954.
• [9] Induction of CYP3As in HepG2 cells by several drugs. Association between induction of CYP3A4 and expression of glucocorticoid receptor. Biol Pharm Bull. 2003 Apr;26(4):510-7.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Induction and regulation of xenobiotic-metabolizing cytochrome P450s in the human A549 lung adenocarcinoma cell line. Am J Respir Cell Mol Biol. 2000 Mar;22(3):360-6.
• [13] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [14] Characterization of the structural determinants required for potent mechanism-based inhibition of human cytochrome P450 1A1 by cannabidiol. Chem Biol Interact. 2014 May 25;215:62-8.
• [15] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [16] Pyrethroids: cytotoxicity and induction of CYP isoforms in human hepatocytes. Drug Metabol Drug Interact. 2008;23(3-4):211-36.
• [17] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [18] Evaluation of gene induction of drug-metabolizing enzymes and transporters in primary culture of human hepatocytes using high-sensitivity real-time reverse transcription PCR. Yakugaku Zasshi. 2002 May;122(5):339-61.
• [19] Induction of human cytochrome P450 3A enzymes in cultured placental cells by thalidomide and relevance to bioactivation and toxicity. J Toxicol Sci. 2017;42(3):343-348.
• [20] Induction of hepatic CYP3A enzymes by pregnancy-related hormones: studies in human hepatocytes and hepatic cell lines. Drug Metab Dispos. 2013 Feb;41(2):281-90.
• [21] Mechanism-based inactivation of CYP3A by HIV protease inhibitors. J Pharmacol Exp Ther. 2005 Feb;312(2):583-91.
• [22] Use of mRNA expression to detect the induction of drug metabolising enzymes in rat and human hepatocytes. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):86-96.
• [23] Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol Pharmacol. 1996 Feb;49(2):311-8.
• [24] Regulation of CYP3A5 by glucocorticoids and cigarette smoke in human lung-derived cells. J Pharmacol Exp Ther. 2003 Feb;304(2):745-52.
• [25] Regulation of CYP3A genes by glucocorticoids in human lung cells. F1000Res. 2013 Aug 13;2:173.
• [26] Bioactivation of the tricyclic antidepressant amitriptyline and its metabolite nortriptyline to arene oxide intermediates in human liver microsomes and recombinant P450s. Chem Biol Interact. 2008 May 9;173(1):59-67.
• [27] Dabrafenib inhibits ABCG2 and cytochrome P450 isoenzymes; potential implications for combination anticancer therapy. Toxicol Appl Pharmacol. 2022 Jan 1;434:115797. doi: 10.1016/j.taap.2021.115797. Epub 2021 Nov 13.
• [28] Metabolism of alfentanil by cytochrome p4503a (cyp3a) enzymes. Drug Metab Dispos. 2005 Mar;33(3):303-11.
• [29] Differential mechanism-based inhibition of CYP3A4 and CYP3A5 by verapamil. Drug Metab Dispos. 2005 May;33(5):664-71.
• [30] Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and metabolites. Xenobiotica. 2002 Oct;32(10):863-78.
• [31] Sulforaphane- and phenethyl isothiocyanate-induced inhibition of aflatoxin B1-mediated genotoxicity in human hepatocytes: role of GSTM1 genotype and CYP3A4 gene expression. Toxicol Sci. 2010 Aug;116(2):422-32.
• [32] U0126, a mitogen-activated protein kinase kinase 1 and 2 (MEK1 and 2) inhibitor, selectively up-regulates main isoforms of CYP3A subfamily via a pregnane X receptor (PXR) in HepG2 cells. Arch Toxicol. 2014 Dec;88(12):2243-59.
• [33] Regulation of cutaneous drug-metabolizing enzymes and cytoprotective gene expression by topical drugs in human skin in vivo. Br J Dermatol. 2006 Aug;155(2):275-81.
• [34] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [35] Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation. Arch Toxicol. 2022 Jan;96(1):259-285. doi: 10.1007/s00204-021-03160-7. Epub 2021 Oct 13.
• [36] Modulation of the xenobiotic transformation system and inflammatory response by ochratoxin A exposure using a co-culture system of Caco-2 and HepG2 cells. Food Chem Toxicol. 2015 Dec;86:245-52.
• [37] Butyrate interacts with benzo[a]pyrene to alter expression and activities of xenobiotic metabolizing enzymes involved in metabolism of carcinogens within colon epithelial cell models. Toxicology. 2019 Jan 15;412:1-11.
• [38] Diazinon, chlorpyrifos and parathion are metabolised by multiple cytochromes P450 in human liver. Toxicology. 2006 Jul 5;224(1-2):22-32.
• [39] No activation of human pregnane X receptor by hyperforin-related phloroglucinols. J Pharmacol Exp Ther. 2014 Mar;348(3):393-400.
• [40] 3-Hydroxyflavone and structural analogues differentially activate pregnane X receptor: Implication for inflammatory bowel disease. Pharmacol Res. 2015 Oct;100:64-72.
• [41] Troglitazone thiol adduct formation in human liver microsomes: enzyme kinetics and reaction phenotyping. Drug Metab Lett. 2008 Aug;2(3):184-9. doi: 10.2174/187231208785425773.
• [42] O-demethylation of epipodophyllotoxins is catalyzed by human cytochrome P450 3A4. Mol Pharmacol. 1994 Feb;45(2):352-8.
• [43] Interindividual variation in relative CYP1A2/3A4 phenotype influences susceptibility of clozapine oxidation to cytochrome P450-specific inhibition in human hepatic microsomes. Drug Metab Dispos. 2008 Dec;36(12):2547-55. doi: 10.1124/dmd.108.023671. Epub 2008 Sep 22.
• [44] The involvement of CYP3A4 and CYP2C9 in the metabolism of 17 alpha-ethinylestradiol. Drug Metab Dispos. 2004 Nov;32(11):1209-12.
• [45] Effect of polymorphic CYP3A5 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects. J Clin Pharmacol. 2007 Jan;47(1):87-93. doi: 10.1177/0091270006295063.
• [46] Associations between drug metabolism genotype, chemotherapy pharmacokinetics, and overall survival in patients with breast cancer. J Clin Oncol. 2005 Sep 1;23(25):6117-25. doi: 10.1200/JCO.2005.06.075. Epub 2005 Aug 8.
• [47] Contribution of CYP3A5 to hepatic and renal ifosfamide N-dechloroethylation. Drug Metab Dispos. 2005 Jul;33(7):1074-81. doi: 10.1124/dmd.104.002279. Epub 2005 Apr 8.
• [48] Participation of CYP2C8 and CYP3A4 in the N-demethylation of imatinib in human hepatic microsomes. Br J Pharmacol. 2010 Nov;161(5):1059-69. doi: 10.1111/j.1476-5381.2010.00946.x.
• [49] Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1alpha,25-dihydroxyvitamin D(3): implications for drug-induced osteomalacia. Mol Pharmacol. 2006 Jan;69(1):56-65.
• [50] Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study. Pharmacogenet Genomics. 2009 Oct;19(10):800-12. doi: 10.1097/FPC.0b013e3283317ab5.
• [51] Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem. 2005 Aug;51(8):1374-81.
• [52] Variability of CYP3A7 expression in human fetal liver. J Pharmacol Exp Ther. 2005 Aug;314(2):626-35. doi: 10.1124/jpet.105.086504. Epub 2005 Apr 21.
• [53] Apoptosis contributes to the cytotoxicity induced by amodiaquine and its major metabolite N-desethylamodiaquine in hepatic cells. Toxicol In Vitro. 2020 Feb;62:104669. doi: 10.1016/j.tiv.2019.104669. Epub 2019 Oct 16.
• [54] Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos. 2004 Dec;32(12):1434-45. doi: 10.1124/dmd.104.001313. Epub 2004 Sep 21.
• [55] Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. CMAJ. 2006 Jun 6;174(12):1715-22. doi: 10.1503/cmaj.060664.
• [56] The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone. Arch Toxicol. 2018 Jun;92(6):1969-1981. doi: 10.1007/s00204-018-2196-x. Epub 2018 Apr 3.
• [57] Comparing antihypertensive effect and plasma ciclosporin concentration between amlodipine and valsartan regimens in hypertensive renal transplant patients receiving ciclosporin therapy. Am J Cardiovasc Drugs. 2011 Dec 1;11(6):401-9. doi: 10.2165/11593800-000000000-00000.
• [58] Polymorphisms of drug-metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa. Br J Clin Pharmacol. 2009 Jan;67(1):50-60. doi: 10.1111/j.1365-2125.2008.03321.x. Epub 2008 Nov 17.
• [59] Effect of genetic variations on ticagrelor plasma levels and clinical outcomes. Eur Heart J. 2015 Aug 1;36(29):1901-12.
• [60] Identification and phenotype characterization of two CYP3A haplotypes causing different enzymatic capacity in fetal livers. Clin Pharmacol Ther. 2005 Apr;77(4):259-70.
• [61] Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes. Drug Metab Dispos. 2005 Apr;33(4):500-7.
• [62] The relative role of CYP3A4 and CYP3A5 in eplerenone metabolism. Toxicol Lett. 2019 Oct 15;315:9-13.
• [63] Mechanism-Based Inactivation of Cytochrome P450 3A4 and 3A5 by the Fibroblast Growth Factor Receptor Inhibitor Erdafitinib. Chem Res Toxicol. 2021 Jul 19;34(7):1800-1813. doi: 10.1021/acs.chemrestox.1c00178. Epub 2021 Jun 30.
• [64] Vitamin E analogues differentially inhibit human cytochrome P450 3A (CYP3A)-mediated oxidative metabolism of lithocholic acid: Impact of -tocotrienol on lithocholic acid cytotoxicity. Toxicology. 2019 Jul 1;423:62-74. doi: 10.1016/j.tox.2019.05.005. Epub 2019 May 15.
• [65] Development of HepG2-derived cells expressing cytochrome P450s for assessing metabolism-associated drug-induced liver toxicity. Chem Biol Interact. 2016 Aug 5;255:63-73. doi: 10.1016/j.cbi.2015.10.009. Epub 2015 Oct 22.
• [66] Characterization of the cytochrome P-450 gene family responsible for the N-dealkylation of the ergot alkaloid CQA 206-291 in humans. Drug Metab Dispos. 1992 Jan-Feb;20(1):56-63.
• [67] Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J Clin Oncol. 2005 Feb 20;23(6):1078-87. doi: 10.1200/JCO.2005.09.119.
• [68] The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes. Arch Toxicol. 2018 Mar;92(3):1099-1112.
• [69] Identification of Quinone Methide Intermediate Resulting from Metabolic Activation of Icaritin in Vitro and in Vivo. Chem Res Toxicol. 2019 Jun 17;32(6):969-973. doi: 10.1021/acs.chemrestox.8b00418. Epub 2019 Apr 9.
• [70] Identification of human cytochrome P450 isozymes involved in the oxidative metabolism of carfentanil. Toxicol Lett. 2021 Jun 1;343:28-33. doi: 10.1016/j.toxlet.2021.02.017. Epub 2021 Feb 27.
• [71] Pulmonary toxicity and metabolic activation of tetrandrine in CD-1 mice. Chem Res Toxicol. 2011 Dec 19;24(12):2142-52. doi: 10.1021/tx200290s. Epub 2011 Nov 11.
• [72] Chemical Reactivity of Aloe-Emodin and Its Hydroxylation Metabolites to Thiols. Chem Res Toxicol. 2019 Feb 18;32(2):234-244. doi: 10.1021/acs.chemrestox.8b00248. Epub 2019 Feb 6.
• [73] In vitro metabolism of helenalin and its inhibitory effect on human cytochrome P450 activity. Arch Toxicol. 2022 Mar;96(3):793-808. doi: 10.1007/s00204-021-03218-6. Epub 2022 Jan 6.
• [74] Ipso substitution of bisphenol A catalyzed by microsomal cytochrome P450 and enhancement of estrogenic activity. Toxicol Lett. 2011 May 30;203(1):92-5. doi: 10.1016/j.toxlet.2011.03.010. Epub 2011 Mar 23.
• [75] Cytochrome P450-mediated activation of the fragrance compound geraniol forms potent contact allergens. Toxicol Appl Pharmacol. 2008 Dec 1;233(2):308-13. doi: 10.1016/j.taap.2008.08.014. Epub 2008 Sep 10.
• [76] Mechanism of inactivation of human cytochrome P450 2B6 by phencyclidine. Drug Metab Dispos. 2006 Sep;34(9):1523-9. doi: 10.1124/dmd.106.010579. Epub 2006 Jun 16.
• [77] In vitro metabolism of naphthalene by human liver microsomal cytochrome P450 enzymes. Drug Metab Dispos. 2006 Jan;34(1):176-83. doi: 10.1124/dmd.105.005785. Epub 2005 Oct 21.
• [78] Foetal and adult human CYP3A isoforms in the bioactivation of organophosphorothionate insecticides. Toxicol Lett. 2006 Dec 15;167(3):245-55. doi: 10.1016/j.toxlet.2006.10.006. Epub 2006 Oct 24.
• [79] Involvement of CYP3A4/5 and CYP2D6 in the metabolism of aconitine using human liver microsomes and recombinant CYP450 enzymes. Toxicol Lett. 2011 Apr 10;202(1):47-54. doi: 10.1016/j.toxlet.2011.01.019. Epub 2011 Jan 28.
• [80] Metabolism of 1,8-cineole by human cytochrome P450 enzymes: identification of a new hydroxylated metabolite. Biochim Biophys Acta. 2005 Apr 15;1722(3):304-11. doi: 10.1016/j.bbagen.2004.12.019. Epub 2005 Jan 17.
• [81] Flavonoids diosmetin and luteolin inhibit midazolam metabolism by human liver microsomes and recombinant CYP 3A4 and CYP3A5 enzymes. Biochem Pharmacol. 2008 Mar 15;75(6):1426-37. doi: 10.1016/j.bcp.2007.11.012. Epub 2007 Dec 4.