Cytochrome P450 (CYP) Gene Superfamily

Abstract

Cytochrome P450, named in the 1960s as a ‘chromatic (coloured) pigment in the cell’ having an absorption maximum of 450 nm when reduced and bound to carbon monoxide, was originally thought to be a single enzyme. P450 was correlated with drug and steroid metabolism; eventually, P450 was recognised to comprise an ancient gene superfamily encoding numerous ubiquitous enzymes that participate in countless essential life processes. Almost 55 000 P450 genes have now been named across all kingdoms of life. Nearly all eukaryotes require sterols in their membranes for essential fluidity and lipid‐packing properties; CYP51 (sterol 14α‐demethylase) synthesises these sterols and, therefore, is fundamental to eukaryotic life and most likely the ancestral P450 gene from which all others were derived. Cytochromes P450 evolved novel functions in chordates, leading to the beginning of steroid hormones. In conjunction with steroid hormone receptors, these novel regulatory pathways distinguish chordates from other animals. Among human's 57 functional CYP genes, DNA variants can cause a number of inborn errors of metabolism, other clinical diseases, and important differences in drug response.

Key Concepts

  • Cytochromes P450 (CYPs) are haem‐containing membrane proteins in the endoplasmic reticulum (ER) or mitochondrial inner membrane.
  • Most CYPs require a source of electrons from an electron transfer chain to function: NADPH‐cytochrome P450 oxidoreductase (POR) in ER and ferredoxin (FDX) plus ferredoxin reductase (FDXR) in mitochondria.
  • CYP functions can be divided into oxidation/reduction of endogenous compounds and foreign chemicals (e.g. drugs, environmental pollutants).
  • Endogenous P450 substrates include mostly lipids (steroids, lanosterol, bile acids, vitamin D, retinoic acid, eicosanoids and other lipid mediators), fatty acids and haem breakdown products.
  • As of 2017, at least six of 57 human P450s still remain ‘orphans’ without agreed‐upon identifiable substrates.
  • Cytochromes P450 in humans (and most vertebrates) are divided into 18 CYP gene families – based on amino acid sequence similarity.
  • CYP gene polymorphisms can alter a person's ability to metabolise drugs (poor, intermediate, efficient or ultrarapid metabolisers).
  • Human CYP3A4 and CYP2D6 are the two major drug‐metabolising enzymes. Removal of mouse Cyp genes and replacement with their human CYP orthologous genes will lead to a better understanding of P450 metabolism that is relevant to clinical pharmacology.
  • Alterations in CYP drug metabolism are often responsible for adverse drug reactions – especially when multiple drugs are taken.
  • Triazole antifungal drugs (ketoconazole, fluconazole and itraconazole) target the CYP51 required for fungal sterol biosynthesis; mutations in this gene can lead to triazole drug resistance.

Keywords: metabolism of fatty acids; cholesterol; steroids; retinoids; vitamin D derivatives; bile acids; eicosanoids and other lipid mediators; environmental pollutant metabolism; drug metabolism; monooxygenases

Figure 1. Structural alignment, comparing human CYP2A6 with Bacillus megaterium CYP102A1. The structures represent a VAST (Vector Alignment Search Tool) 3D comparison of human CYP2A6 in blue (PDB code 1Z11, MMDB code 34695) and B. megaterium CYP102A1 in fuchsia (Bm3) (PDB code 3KX5, MMDB code 82192). The P450 part of Bm3 is an E‐like P450 (most like eukaryotic P450s), and, among the VAST alignments, the CYP2A6 structure was the best match to Bm3 from human. There is only 18% amino acid sequence identity.
close

References

Baker ME, Nelson DR and Studer RA (2015) Origin of the response to adrenal and sex steroids: roles of promiscuity and co‐evolution of enzymes and steroid receptors. Journal of Steroid Biochemistry and Molecular Biology 151: 12–24.

Bardowell SA, Duan F, Manor D, Swanson JE and Parker RS (2012) Disruption of mouse cytochrome P450 4F14 (Cyp4f14 gene) causes severe perturbations in vitamin E metabolism. Journal of Biological Chemistry 287: 26077–26086.

Bernhardt R (2016) The potential of targeting CYP11B. Expert Opinion on Therapeutic Targets 20: 923–934.

Bird IM and Abbott DH (2016) The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature. Journal of Steroid Biochemistry and Molecular Biology 163: 136–146.

Cathcart MC, Reynolds JV, O'Byrne KJ and Pidgeon GP (2010) Role of prostacyclin synthase and thromboxane synthase signaling in development and progression of cancer. Biochimica et Biophysica Acta 1805: 153–166.

Chen C and Wang DW (2015) Cytochrome P450 CYP2 family: epoxygenase role in inflammation and cancer. Advances in Pharmacology 74: 193–221.

Choi JY and Roush WR (2017) Structure‐based design of CYP51 inhibitors. Current Topics in Medicinal Chemistry 17: 30–39.

Cooke PS, Nanjappa MK, Ko C, Prins GS and Hess RA (2017) Estrogens in male physiology. Physiological Reviews 97: 995–1043.

Damiri B, Holle E, Yu X and Baldwin WS (2012) Lentiviral‐mediated RNAi knockdown yields a novel mouse model for studying CYP2B function. Toxicological Sciences 125: 368–381.

Divanovic S, Dalli J, Jorge‐Nebert LF, et al. (2013) Contributions of the three CYP1 monooxygenases to pro‐inflammatory and inflammation‐resolution lipid mediator pathways. Journal of Immunology 191: 3347–3357.

Dong H, Dalton TP, Miller ML, et al. (2009) Knock‐in mouse lines expressing either mitochondrial or microsomal CYP1A1: differing responses to dietary benzo[a]pyrene as proof of principle. Molecular Pharmacology 75: 555–567.

Enright JM, Toomey MB, Sato SY, et al. (2015) CYP27C1 red‐shifts the spectral sensitivity of photoreceptors by converting Vitamin A1 into A2. Current Biology 25: 3048–3057.

Feng CW, Bowles J and Koopman P (2014) Control of mammalian germ cell entry into meiosis. Molecular and Cellular Endocrinology 382: 488–497.

Fontana P, Zufferey A, Daali Y and Reny JL (2014) Antiplatelet therapy: targeting the TXA2 pathway. Journal of Cardiovascular Translational Research 7: 29–38.

Han J, Kim DH, Seo JS, et al. (2017) Assessing identity and expression level of cytochrome P450 20A1 (CYP20A1) gene in the BPA‐, BDE‐47, and WAF‐exposed copepods Tigriopus japonicus and Paracyclopina nana. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 193: 42–49.

Heverin M, Ali Z, Olin M, et al. (2017) On the regulatory importance of 27‐hydroxycholesterol in mouse liver. Journal of Steroid Biochemistry and Molecular Biology 169: 10–21.

Hill M, Paskova A, Kanceva R, et al. (2014) Steroid profiling in pregnancy: a focus on the human fetus. Journal of Steroid Biochemistry and Molecular Biology 139: 201–222.

Johnson AL, Edson KZ, Totah RA and Rettie AE (2015) Cytochrome P450 ω‐hydroxylases in inflammation and cancer. Advances in Pharmacology 74: 223–262.

Joshi SR, Lakhkar A, Dhagia V, et al. (2016) Cyp2c44 gene disruption exacerbated pulmonary hypertension and heart failure in female but not male mice. Pulmonary Circulation 6: 360–368.

Katoh M, Tateno C, Yoshizato K and Yokoi T (2008) Chimeric mice with humanized liver. Toxicology 246: 9–17.

Keber R, Motaln H, Wagner KD, et al. (2011) Mouse knockout of the cholesterogenic cytochrome P450 lanosterol 14alpha‐demethylase (Cyp51) resembles Antley‐Bixler syndrome. Journal of Biological Chemistry 286: 29086–29097.

Keber R, Acimovic J, Majdic G, et al. (2013) Male germ cell‐specific knockout of cholesterogenic cytochrome P450 lanosterol 14α‐demethylase gene (Cyp51a1). Journal of Lipid Research 54: 1653–1661.

Kelly SL and Kelly DE (2013) Microbial cytochromes P450: biodiversity and biotechnology. Where do cytochromes P450 come from, what do they do and what can they do for us? Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 368: 20120476.

Koyama S and Kato T (2016) Pathophysiology of cerebrotendinous xanthomatosis. Rinshō Shinkeigaku 56: 821–826.

Kramlinger VM, Nagy LD, Fujiwara R, et al. (2016) Human cytochrome P450 27C1 catalyzes 3,4‐desaturation of retinoids. FEBS Letters 590: 1304–1312.

Kwon YJ, Baek HS, Ye DJ, et al. (2016) CYP1B1 enhances cell proliferation and metastasis through induction of EMT and activation of WNT/β‐catenin signaling via Sp1 upregulation. PLoS One 11: e0151598.

Lopes RJ, Johnson JD, Toomey MB, et al. (2016) Genetic basis for red coloration in birds. Current Biology 26: 1427–1434.

Manousaki D, Dudding T, Haworth S, et al. (2017) Low‐frequency synonymous coding variant in CYP2R1 has large effects on vitamin D levels and risk of multiple sclerosis. American Journal of Human Genetics 101: 227–238.

Martin A and Quarles LD (2012) Evidence for FGF23 involvement in a bone‐kidney axis regulating bone mineralization, systemic phosphate, and vitamin D homeostasis. Adv. Exp. Med. Biol. 728: 65–83.

Matsunobu T, Okuno T, Yokoyama C and Yokomizo T (2013) Thromboxane A synthase‐independent production of 12‐hydroxyheptadecatrienoic acid, a BLT2 ligand. Journal of Lipid Research 54: 2979–2987.

Mitra R and Goodman OB Jr (2015) CYP3A5 regulates prostate cancer cell growth by facilitating nuclear translocation of AR. Prostate 75: 527–538.

Moutinho M, Nunes MJ and Rodrigues E (2016) Cholesterol 24‐hydroxylase: brain cholesterol metabolism and beyond. Biochimica et Biophysica Acta 1861: 1911–1920.

Mundy NI, Stapley J, Bennison C, et al. (2016) Red carotenoid coloration in the zebra finch Is controlled by a cytochrome P450 gene cluster. Current Biology 26: 1435–1440.

Nebert DW and Karp CL (2008) Endogenous functions of aryl hydrocarbon receptor (AHR): intersection of cytochrome P450 1 (CYP1)‐metabolized eicosanoids and AHR biology. Journal of Biological Chemistry 283: 36061–36065.

Nebert DW, Shi Z, Galvez‐Peralta M, Uno S and Dragin N (2013a) Oral benzo[a]pyrene: understanding pharmacokinetics, detoxication, and consequences‐‐Cyp1 knockout mouse lines as a paradigm. Molecular Pharmacology 84: 304–313.

Nebert DW, Wikvall K and Miller WL (2013b) Human cytochromes P450 in health and disease. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 368: 20120431.

Nebert DW (2017) Aryl hydrocarbon receptor (AHR): “pioneer member” of the basic‐helix/loop/helix per‐Arnt‐sim (bHLH/PAS) family of “sensors” of foreign and endogenous signals. Progress in Lipid Research 67: 38–57.

Nelson DR (2009) The cytochrome P450 homepage. Human Genomics 4: 59–65.

Nelson DR (2018) Cytochrome P450 diversity in the tree of life. Biochimica et Biophysica Acta Proteins and Proteomics. 1866: 141–154. PMID: 28502748; 10.1016/j.bbapap.2017.05.003.

Ng DS, Lai TY, Ng TK and Pang CP (2016) Genetics of Bietti crystalline dystrophy. Asia Pacific Journal of Ophthalmology (Phila) 5: 245–252.

Osanai M (2017) Cellular retinoic acid bioavailability in various pathologies and its therapeutic implication. Pathology International 67: 281–291.

Saleheen D, Natarajan P, Armean IM, et al. (2017) Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature 544: 235–239.

Scheer N, Kapelyukh Y, Chatham L, et al. (2012a) Generation and characterization of novel cytochrome P450 Cyp2c gene cluster knockout and CYP2C9‐humanized mouse lines. Molecular Pharmacology 82: 1022–1029.

Scheer N, Kapelyukh Y, McEwan J, et al. (2012b) Modeling human cytochrome P450 2D6 metabolism and drug‐drug interaction by a novel panel of knockout and humanized mouse lines. Molecular Pharmacology 81: 63–72.

Scheer N, McLaughlin LA, Rode A, et al. (2014) Deletion of 30 murine cytochrome P450 genes results in viable mice with compromised drug metabolism. Drug Metabolism and Disposition 42: 1022–1030.

Scheer N, Kapelyukh Y, Rode A, et al. (2015) Defining human pathways of drug metabolism in vivo through the development of a multiple‐humanized mouse model. Drug Metabolism and Disposition 43: 1679–1690.

Slominski AT, Li W, Kim TK, et al. (2015) Novel activities of CYP11A1 and their potential physiological significance. Journal of Steroid Biochemistry and Molecular Biology 151: 25–37.

Stevison F, Jing J, Tripathy S and Isoherranen N (2015) Role of retinoic acid‐metabolizing cytochrome P450s, CYP26, in inflammation and cancer. Advances in Pharmacology 74: 373–412.

Stiles AR, Kozlitina J, Thompson BM, et al. (2014) Genetic, anatomic, and clinical determinants of human serum sterol and vitamin D levels. Proceedings of the National Academy of Sciences of the United States of America 111: E4006–E4014.

Sugiura K and Akiyama M (2015) Update on autosomal recessive congenital ichthyosis: mRNA analysis using hair samples is a powerful tool for genetic diagnosis. Journal of Dermatological Science 79: 4–9.

Sun MY, Linsenbardt AJ, Emnett CM, et al. (2016) 24(S)‐Hydroxycholesterol as a modulator of neuronal signaling and survival. The Neuroscientist 22: 132–144.

Twyman H, Valenzuela N, Literman R, Andersson S and Mundy NI (2016) Seeing red to being red: conserved genetic mechanism for red cone oil droplets and co‐option for red coloration in birds and turtles. Proceedings of the Biological Sciences 283: 1836. pii: 20161208. DOI: 10.1098/rspb.2016.1208.

Walsh NC, Kenney LL, Jangalwe S, et al. (2017) Humanized mouse models of clinical disease. Annual Review of Pathology 12: 187–215.

Wang WH, Zhang C, Lin DH, et al. (2014) CYP2C44 epoxygenase in mouse kidney collecting duct is essential for the high K+ intake‐induced anti‐hypertensive effect. American Journal of Physiology. Renal Physiology 307: F453–F460.

Wei Y, Li L, Zhou X, et al. (2013) Generation and characterization of a novel Cyp2a(4/5)bgs‐null mouse model. Drug Metabolism and Disposition 41: 132–140.

Winslow V, Vaivoda R, Vasilyev A, et al. (2014) Altered leukotriene B4 metabolism in CYP4F18‐deficient mice does not impact inflammation following renal ischemia. Biochimica et Biophysica Acta 1841: 868–879.

Wu H, Liu Z, Ling G, Lawrence D and Ding X (2013) Transcriptional suppression of CYP2A13 expression by lipopolysaccharide in cultured human lung cells and lungs of a CYP2A13‐humanized mouse model. Toxicological Sciences 135: 476–485.

Yang H and Duan Z (2016) Bile acids and the potential role in primary biliary cirrhosis. Digestion 94: 145–153.

Zhao H, Pearson EK, Brooks DC, et al. (2012) A humanized pattern of aromatase expression is associated with mammary hyperplasia in mice. Endocrinology 153: 2701–2713.

Zhou X, Zhuo X, Xie F, et al. (2010) Role of CYP2A5 in the clearance of nicotine and cotinine: insights from studies on a Cyp2a5‐null mouse model. Journal of Pharmacology and Experimental Therapeutics 332: 578–587.

Further Reading

Cathcart MC, Reynolds JV, O'Byrne KJ and Pidgeon GP (2010) Role of prostacyclin synthase and thromboxane synthase signaling in development and progression of cancer. Biochimica et Biophysica Acta 1805: 153–166.

Choi JY and Roush WR (2017) Structure‐based design of CYP51 inhibitors. Current Topics in Medicinal Chemistry 17: 30–39.

Cooke PS, Nanjappa MK, Ko C, Prins GS and Hess RA (2017) Estrogens in male physiology. Physiological Reviews 97: 995–1043.

Johnson AL, Edson KZ, Totah RA and Rettie AE (2015) Cytochrome P450 ω‐hydroxylases in inflammation and cancer. Advances in Pharmacology 74: 223–262.

Nebert DW, Wikvall K and Miller WL (2013b) Human cytochromes P450 in health and disease. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 368: 20120431.

Nebert DW (2017) Aryl hydrocarbon receptor (AHR): “pioneer member” of the basic‐helix/loop/helix per‐Arnt‐sim (bHLH/PAS) family of “sensors” of foreign and endogenous signals. Progress in Lipid Research 67: 38–57.

Nelson DR (2009) The cytochrome P450 homepage. Human Genomics 4: 59–65.

Nelson DR (2017) Cytochrome P450 diversity in the tree of life. Biochimica et Biophysica Acta Proteins and Proteomics. 1866: 141–154. PMID: 28502748; 10.1016/j.bbapap.2017.05.003.

Scheer N, McLaughlin LA, Rode A, et al. (2014) Deletion of 30 murine cytochrome P450 genes results in viable mice with compromised drug metabolism. Drug Metabolism and Disposition 42: 1022–1030.

Walsh NC, Kenney LL, Jangalwe S, et al. (2017) Humanized mouse models of clinical disease. Annual Review of Pathology 12: 187–215.

Web Links

Additional links to P450 resources http://drnelson.uthsc.edu/matrix.html.

Cytochrome P450 Homepage (http://drnelson.uthsc.edu/CytochromeP450.html).

Human Cytochrome P450 Alleles Nomenclature Committee Website https://www.PharmVar.org/.

Human Cytochrome P450 Master Table http://drnelson.uthsc.edu/human.P450.table.html.

More than 700 links to human P450 data can be found at the Cytochrome P450 Human Master Table http://drnelson.uthsc.edu/human.P450.table.html.

Mouse P450 data are available at the Cytochrome P450 Mouse Master Table http://drnelson.uthsc.edu/mouse.master.table.html.

Rat P450 data are available at the Cytochrome P450 Rat Master Table http://drnelson.uthsc.edu/rat.master.table.html.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Nelson, David R, and Nebert, Daniel W(Jan 2018) Cytochrome P450 (CYP) Gene Superfamily. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005667.pub3]