CYP3A
| Cytochrome P450 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Mechanism of CYP450 enzymatic catalysis | |||||||||
| Identifiers | |||||||||
| Symbol | p450 | ||||||||
| Pfam | PF00067 | ||||||||
| InterPro | IPR001128 | ||||||||
| PROSITE | PDOC00081 | ||||||||
| SCOP2 | 2cpp / SCOPe / SUPFAM | ||||||||
| OPM superfamily | 39 | ||||||||
| OPM protein | 2bdm | ||||||||
| CDD | cd00302 | ||||||||
| Membranome | 265 | ||||||||
| |||||||||
Cytochrome P450, family 3, subfamily A, also known as CYP3A, is a human gene locus.[1][2] A homologous locus is found in mice.[3] These genes encode monooxygenases which catalyze many reactions involved in the synthesis of cholesterol, steroids and other lipids as well as drug metabolism.
The CYP3A locus includes all the known members of the 3A subfamily of the cytochrome P450 superfamily of genes. The CYP3A cluster consists of four genes:
The region also contains four pseudogenes:
as well as several extra exons which may or may not be included in transcripts produced from this region. Previously another CYP3A member, CYP3A3, was thought to exist; however, it is now thought that this sequence represents a transcript variant of CYP3A4.[1]
Structure
[edit]Structurally, the key to the CYP3A enzyme’s large range of activity is the heme cofactor and the P450 protein fold, an oxidation reaction through molecular oxygen and NADPH.[4] The enzyme binds to the substrate, where electrons are accepted from NADPH, and a reactive iron-oxo species inserts an oxygen atom into the substrate, making the metabolized drug more polar.[4] The active site is large and flexible allowing it to bind to a wide variety of substrates, and this specifically occurs due to secondary structure elements like helices and loops that can accommodate bulky ligands.[5] Another important feature of the active site is its ability to accommodate multiple substrates at once leading to cooperative interactions, making the CYP3A family often more potent than other types of CYP450 isoforms.[6]
Function
[edit]Endogenous substrate catabolism
[edit]The CYP3A subfamily of enzymes is integral to the metabolism of a variety of endogenous compounds, thereby contributing to the maintenance of physiological homeostasis. These enzymes, including CYP3A4, CYP3A5, and CYP3A7, are involved in the catabolism of steroid hormones, metabolism of bile acids, cholesterol, arachidonic acid, vitamin D, and other lipids.[7][8][9] For example, CYP3A4 catalyzes the conversion of arachidonic acid into epoxyeicosatrienoic acids (EETs), which have roles in blood pressure regulation, anti-inflammatory responses, and cell proliferation.[7] CYP3A enzymes also participate in the termination of steroid hormone action and the detoxification of bile acids, highlighting their significance in hormonal regulation and metabolic balance.[9] Variations in CYP3A expression, influenced by genetic and physiological factors, can alter the metabolism of these endogenous substrates, potentially impacting disease susceptibility and progression.[7]
Xenobiotic metabolism
[edit]The CYP3A subfamily is critically involved in the detoxification and biotransformation of xenobiotics, including a wide array of clinically used drugs, environmental chemicals, toxins, and dietary compounds.[10][11] Among the isoforms, CYP3A4 is the most abundant in the adult human liver and intestine and is responsible for metabolizing approximately 30–50% of all prescription drugs, including acetaminophen, codeine, cyclosporine, diazepam, and erythromycin.[9] These enzymes catalyze oxidative reactions that enhance the water solubility of lipophilic substances, thereby facilitating their elimination from the body.[10]
CYP3A-mediated metabolism can lead to either drug inactivation or bioactivation, resulting in pharmacologically active or potentially toxic metabolites. Expression and activity levels of CYP3A enzymes vary significantly among individuals due to genetic polymorphisms and environmental factors, which can influence drug efficacy, safety, and the likelihood of adverse drug interactions.[7][9]
The CYP3A subfamily also plays a central role in phase I metabolism, introducing polar functional groups that increase water solubility and promote excretion from the body. These enzymes account for the oxidative metabolism of roughly 30% of all clinical drugs, including statins and chemotherapeutics.[12]
Regulation of CYP3A enzymes plays a significant role in pharmacokinetics, particularly in the context of drug-drug interactions. Both inhibition and induction of these enzymes can substantially alter drug metabolism.[13] For example, Paxlovid combines Nirmatrelvir, a Mpro-protease inhibitor, with Ritonavir, a potent CYP3A inhibitor that slows the breakdown of Nirmatrelvir, enhancing its therapeutic effect.[14]
References
[edit]- ^ a b "Entrez Gene: CYP3A cytochrome P450, family 3, subfamily A".
- ^ Gellner K, Eiselt R, Hustert E, Arnold H, Koch I, Haberl M, et al. (March 2001). "Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene". Pharmacogenetics. 11 (2): 111–121. doi:10.1097/00008571-200103000-00002. PMID 11266076.
- ^ Zaphiropoulos PG (June 2003). "A map of the mouse Cyp3a locus". DNA Sequence : The Journal of DNA Sequencing and Mapping. 14 (3): 155–162. doi:10.1080/1042517031000089478. PMID 14509827. S2CID 21317627.
- ^ a b Guengerich FP (2007). "Mechanisms of cytochrome P450 substrate oxidation: MiniReview". Journal of Biochemical and Molecular Toxicology. 21 (4): 163–168. doi:10.1002/jbt.20174. ISSN 1099-0461. PMID 17936929.
- ^ Sevrioukova IF, Poulos TL (2013-03-07). "Understanding the mechanism of cytochrome P450 3A4: recent advances and remaining problems". Dalton Transactions. 42 (9). Cambridge, England: 3116–3126. doi:10.1039/c2dt31833d. ISSN 1477-9234. PMC 3787833. PMID 23018626.
- ^ Zhao M, Ma J, Li M, Zhang Y, Jiang B, Zhao X, et al. (2021-11-26). "Cytochrome P450 Enzymes and Drug Metabolism in Humans". International Journal of Molecular Sciences. 22 (23): 12808. doi:10.3390/ijms222312808. ISSN 1422-0067. PMC 8657965. PMID 34884615.
- ^ a b c d Fujino C, Sanoh S, Katsura T (2021). "Variation in Expression of Cytochrome P450 3A Isoforms and Toxicological Effects: Endo- and Exogenous Substances as Regulatory Factors and Substrates". Biological & Pharmaceutical Bulletin. 44 (11): 1617–1634. doi:10.1248/bpb.b21-00332. PMID 34719640.
- ^ Klyushova LS, Perepechaeva ML, Grishanova AY (October 2022). "The Role of CYP3A in Health and Disease". Biomedicines. 10 (11): 2686. doi:10.3390/biomedicines10112686. PMC 9687714. PMID 36359206.
- ^ a b c d Zhang Y, Wang Z, Wang Y, Jin W, Zhang Z, Jin L, et al. (2024). "CYP3A4 and CYP3A5: the crucial roles in clinical drug metabolism and the significant implications of genetic polymorphisms". PeerJ. 12: e18636. doi:10.7717/peerj.18636. PMC 11625447. PMID 39650550.
- ^ a b Yaqoob A, Rehman Q, Rehman K, Akash MS, Hussain I, Ahmad R (January 2022). "Role of drug-metabolizing enzymes in biotransformation of drugs.". Biochemistry of Drug Metabolizing Enzymes. Academic Press. pp. 73–108. doi:10.1016/B978-0-323-95120-3.00013-0. ISBN 978-0-323-95120-3.
- ^ Wright WC, Chenge J, Chen T (December 2019). "Structural Perspectives of the CYP3A Family and Their Small Molecule Modulators in Drug Metabolism". Liver Research. 3 (3–4). Beijing, China: 132–142. doi:10.1016/j.livres.2019.08.001. PMC 7418881. PMID 32789028.
- ^ Zanger UM, Schwab M (2013-04-01). "Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation". Pharmacology & Therapeutics. 138 (1): 103–141. doi:10.1016/j.pharmthera.2012.12.007. ISSN 0163-7258. PMID 23333322.
- ^ Hakkola J, Hukkanen J, Turpeinen M, Pelkonen O (2020-11-01). "Inhibition and induction of CYP enzymes in humans: an update". Archives of Toxicology. 94 (11): 3671–3722. Bibcode:2020ArTox..94.3671H. doi:10.1007/s00204-020-02936-7. ISSN 1432-0738. PMC 7603454. PMID 33111191.
- ^ Gerhart J, Cox DS, Singh RS, Chan PL, Rao R, Allen R, et al. (January 2024). "A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir". Clinical Pharmacokinetics. 63 (1): 27–42. doi:10.1007/s40262-023-01339-y. ISSN 1179-1926. PMC 10786959. PMID 38177893.
Further reading
[edit]- Smith G, Stubbins MJ, Harries LW, Wolf CR (December 1998). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 28 (12): 1129–1165. doi:10.1080/004982598238868. PMID 9890157.
- Lamba JK, Lin YS, Schuetz EG, Thummel KE (November 2002). "Genetic contribution to variable human CYP3A-mediated metabolism". Advanced Drug Delivery Reviews. 54 (10): 1271–1294. doi:10.1016/S0169-409X(02)00066-2. PMID 12406645.
- Finta C, Zaphiropoulos PG (December 2000). "The human cytochrome P450 3A locus. Gene evolution by capture of downstream exons". Gene. 260 (1–2): 13–23. doi:10.1016/S0378-1119(00)00470-4. PMID 11137287.
- Miyazawa M, Shindo M, Shimada T (October 2001). "Roles of cytochrome P450 3A enzymes in the 2-hydroxylation of 1,4-cineole, a monoterpene cyclic ether, by rat and human liver microsomes". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 31 (10): 713–723. doi:10.1080/00498250110065595. PMID 11695850. S2CID 41495172.
- Reid JM, Kuffel MJ, Ruben SL, Morales JJ, Rinehart KL, Squillace DP, et al. (September 2002). "Rat and human liver cytochrome P-450 isoform metabolism of ecteinascidin 743 does not predict gender-dependent toxicity in humans". Clinical Cancer Research. 8 (9): 2952–2962. PMID 12231541.
- Martínez C, García-Martín E, Pizarro RM, García-Gamito FJ, Agúndez JA (September 2002). "Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy". British Journal of Cancer. 87 (6): 681–686. doi:10.1038/sj.bjc.6600494. PMC 2364247. PMID 12237780.
- Dowling TC, Briglia AE, Fink JC, Hanes DS, Light PD, Stackiewicz L, et al. (May 2003). "Characterization of hepatic cytochrome p4503A activity in patients with end-stage renal disease". Clinical Pharmacology and Therapeutics. 73 (5): 427–434. doi:10.1016/S0009-9236(03)00056-0. PMID 12732843. S2CID 23774236.
- Sunman JA, Hawke RL, LeCluyse EL, Kashuba AD (March 2004). "Kupffer cell-mediated IL-2 suppression of CYP3A activity in human hepatocytes". Drug Metabolism and Disposition: The Biological Fate of Chemicals. 32 (3): 359–363. doi:10.1124/dmd.32.3.359. PMID 14977871. S2CID 30506452.
- Somogyi AA, Menelaou A, Fullston SV (October 2004). "CYP3A4 mediates dextropropoxyphene N-demethylation to nordextropropoxyphene: human in vitro and in vivo studies and lack of CYP2D6 involvement". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 34 (10): 875–887. doi:10.1080/00498250400008371. PMID 15764408. S2CID 7680532.
- Thompson EE, Kuttab-Boulos H, Yang L, Roe BA, Di Rienzo A (2006). "Sequence diversity and haplotype structure at the human CYP3A cluster". The Pharmacogenomics Journal. 6 (2): 105–114. doi:10.1038/sj.tpj.6500347. PMID 16314882. S2CID 10102745.
- Bochud M, Eap CB, Elston RC, Bovet P, Maillard M, Schild L, et al. (May 2006). "Association of CYP3A5 genotypes with blood pressure and renal function in African families". Journal of Hypertension. 24 (5): 923–929. doi:10.1097/01.hjh.0000222763.84605.4a. PMID 16612255. S2CID 30703443.
- Cheung CY, Op den Buijsch RA, Wong KM, Chan HW, Chau KF, Li CS, et al. (June 2006). "Influence of different allelic variants of the CYP3A and ABCB1 genes on the tacrolimus pharmacokinetic profile of Chinese renal transplant recipients". Pharmacogenomics. 7 (4): 563–574. doi:10.2217/14622416.7.4.563. PMID 16753004.
- Rais N, Chawla YK, Kohli KK (June 2006). "CYP3A phenotypes and genotypes in North Indians". European Journal of Clinical Pharmacology. 62 (6): 417–422. doi:10.1007/s00228-006-0105-3. PMID 16758258. S2CID 24149704.
- Kirby B, Kharasch ED, Thummel KT, Narang VS, Hoffer CJ, Unadkat JD (November 2006). "Simultaneous measurement of in vivo P-glycoprotein and cytochrome P450 3A activities". Journal of Clinical Pharmacology. 46 (11): 1313–1319. doi:10.1177/0091270006292625. PMID 17050796. S2CID 10964615.
- He P, Court MH, Greenblatt DJ, von Moltke LL (November 2006). "Human pregnane X receptor: genetic polymorphisms, alternative mRNA splice variants, and cytochrome P450 3A metabolic activity". Journal of Clinical Pharmacology. 46 (11): 1356–1369. doi:10.1177/0091270006292125. PMID 17050801. S2CID 35139870.
- Watanabe A, Nakamura K, Okudaira N, Okazaki O, Sudo K (July 2007). "Risk assessment for drug-drug interaction caused by metabolism-based inhibition of CYP3A using automated in vitro assay systems and its application in the early drug discovery process". Drug Metabolism and Disposition: The Biological Fate of Chemicals. 35 (7): 1232–1238. doi:10.1124/dmd.107.015016. PMID 17392390. S2CID 11204475.
- Kharasch ED, Walker A, Isoherranen N, Hoffer C, Sheffels P, Thummel K, et al. (October 2007). "Influence of CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of the cytochrome P4503A probes alfentanil and midazolam". Clinical Pharmacology and Therapeutics. 82 (4): 410–426. doi:10.1038/sj.clpt.6100237. PMID 17554244. S2CID 25122764.
