Human cytochromes P450 in health and disease - PubMed (original) (raw)
Review
. 2013 Jan 6;368(1612):20120431.
doi: 10.1098/rstb.2012.0431. Print 2013 Feb 19.
Affiliations
- PMID: 23297354
- PMCID: PMC3538421
- DOI: 10.1098/rstb.2012.0431
Review
Human cytochromes P450 in health and disease
Daniel W Nebert et al. Philos Trans R Soc Lond B Biol Sci. 2013.
Abstract
There are 18 mammalian cytochrome P450 (CYP) families, which encode 57 genes in the human genome. CYP2, CYP3 and CYP4 families contain far more genes than the other 15 families; these three families are also the ones that are dramatically larger in rodent genomes. Most (if not all) genes in the CYP1, CYP2, CYP3 and CYP4 families encode enzymes involved in eicosanoid metabolism and are inducible by various environmental stimuli (i.e. diet, chemical inducers, drugs, pheromones, etc.), whereas the other 14 gene families often have only a single member, and are rarely if ever inducible or redundant. Although the CYP2 and CYP3 families can be regarded as largely redundant and promiscuous, mutations or other defects in one or more genes of the remaining 16 gene families are primarily the ones responsible for P450-specific diseases-confirming these genes are not superfluous or promiscuous but rather are more directly involved in critical life functions. P450-mediated diseases comprise those caused by: aberrant steroidogenesis; defects in fatty acid, cholesterol and bile acid pathways; vitamin D dysregulation and retinoid (as well as putative eicosanoid) dysregulation during fertilization, implantation, embryogenesis, foetogenesis and neonatal development.
Figures
Figure 1.
Schematic of (a) type I P450 and (b) type II P450. FAD, flavin adenine dinucleotide; FDX, ferrodoxin; FDXR, ferrodoxin reductase; FMN, flavin mononucleotide; POR, P450 oxidoreductase; CYB5, cytochrome b5. Scheme copyrighted by WL Miller.
Figure 2.
Scheme to show the relationship of eicosanoid synthesis and degradation, catalysed by cyclooxygenases-1 and -2 (PTGS1, PTGS2), possibly every member of the P450 families CYP1, CYP2, CYP2 and CYP4, plus the six arachidonate lipoxygenases (human ALOX5, ALOX12, ALOX12B, ALOX15, ALOX15B and ALOXE3). All of this metabolism occurs upstream of eicosanoid binding to specific receptors, activity in specific cell types, resulting in innumerable critical life processes. Whereas most eicosanoids are derived via arachidonic acid from ω-6 fatty acids, an important group of resolvins are derived via eicosapentaenoic acid and docosahexaenoic acid from ω-3 fatty acids. EETs, epoxyeicosatrienoic acids; HETEs, hydroxyeicosatetraenoic acids; DHETEs, dihydroxyeicosatrienoic acids; HPETEs, hydroperoxyeicosatetraenoic acids.
Figure 3.
Summary of P450 enzymes in cholesterol and bile acid biosynthesis. Biosynthesis of cholesterol from acetyl-CoA involves approximately 30 enzymatic steps. There is a single P450 (CYP51A1) in cholesterol biosynthesis. In the classic (neutral) pathway of bile acid biosynthesis, cholesterol is converted to two primary bile acids in human liver—cholic acid and chenodeoxycholic acid. In the alternative (acidic) pathway and other pathways involving oxysterols, mainly chenodeoxycholic acid is formed. The key regulated enzymes in the bile acid biosynthetic pathways are CYP7A1, CYP8B1, CYP27A1 and CYP7B1.
Figure 4.
Simplified scheme illustrating the P450 enzymes involved in steroidogenesis. CYB5, cytochrome b5; DHEA, dehydroepiandrosterone.
Figure 5.
Diagram showing the fundamental steps and P450 enzymes involved in vitamin D biosynthesis and degradation pathway. Cholecalciferol (D3) is converted via two steps to make the potent active ligand for vitamin D receptor (VDR). CYP24A1 participates in degradation (at two possible steps), the CYP24A1 gene being activated when Ca2+ levels are sufficient and thus less VDR action is needed.
Similar articles
- 57 varieties: the human cytochromes P450.
Lewis DF. Lewis DF. Pharmacogenomics. 2004 Apr;5(3):305-18. doi: 10.1517/phgs.5.3.305.29827. Pharmacogenomics. 2004. PMID: 15102545 Review. - Cytochrome P450 (CYP) in fish.
Uno T, Ishizuka M, Itakura T. Uno T, et al. Environ Toxicol Pharmacol. 2012 Jul;34(1):1-13. doi: 10.1016/j.etap.2012.02.004. Epub 2012 Feb 17. Environ Toxicol Pharmacol. 2012. PMID: 22418068 Review. - Exploring human CYP4 enzymes: Physiological roles, function in diseases and focus on inhibitors.
Zhou M, Li J, Xu J, Zheng L, Xu S. Zhou M, et al. Drug Discov Today. 2023 May;28(5):103560. doi: 10.1016/j.drudis.2023.103560. Epub 2023 Mar 22. Drug Discov Today. 2023. PMID: 36958639 Review. - Diversity and evolution of the P450 family in arthropods.
Dermauw W, Van Leeuwen T, Feyereisen R. Dermauw W, et al. Insect Biochem Mol Biol. 2020 Dec;127:103490. doi: 10.1016/j.ibmb.2020.103490. Epub 2020 Oct 22. Insect Biochem Mol Biol. 2020. PMID: 33169702
Cited by
- Harnessing Porphyrin Accumulation in Liver Cancer: Combining Genomic Data and Drug Targeting.
Adapa SR, Meshram P, Sami A, Jiang RHY. Adapa SR, et al. Biomolecules. 2024 Aug 7;14(8):959. doi: 10.3390/biom14080959. Biomolecules. 2024. PMID: 39199347 Free PMC article. - Triazine herbicide prometryn alters epoxide hydrolase activity and increases cytochrome P450 metabolites in murine livers via lipidomic profiling.
Sule RO, Morisseau C, Yang J, Hammock BD, Gomes AV. Sule RO, et al. Sci Rep. 2024 Aug 19;14(1):19135. doi: 10.1038/s41598-024-69557-3. Sci Rep. 2024. PMID: 39160161 Free PMC article. - Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption.
Koh YC, Pan MH. Koh YC, et al. ACS Omega. 2024 Jul 9;9(29):31298-31312. doi: 10.1021/acsomega.4c04120. eCollection 2024 Jul 23. ACS Omega. 2024. PMID: 39072055 Free PMC article. Review. - Decoding the Role of CYP450 Enzymes in Metabolism and Disease: A Comprehensive Review.
Hossam Abdelmonem B, Abdelaal NM, Anwer EKE, Rashwan AA, Hussein MA, Ahmed YF, Khashana R, Hanna MM, Abdelnaser A. Hossam Abdelmonem B, et al. Biomedicines. 2024 Jul 2;12(7):1467. doi: 10.3390/biomedicines12071467. Biomedicines. 2024. PMID: 39062040 Free PMC article. Review. - Genetic Insights into Azoospermia and Severe Oligozoospermia: Discovering Seven SNPs through GWAS and In Silico Analysis.
Chatziparasidou A, Kyrgiafini MA, Sarafidou T, Moutou KA, Mamuris Z. Chatziparasidou A, et al. Curr Issues Mol Biol. 2024 Jun 27;46(7):6522-6532. doi: 10.3390/cimb46070389. Curr Issues Mol Biol. 2024. PMID: 39057031 Free PMC article.
References
- Klingenberg M. 1958. Pigments of rat liver microsomes. Arch. Biochem. Biophys. 75, 376–38610.1016/0003-9861(58)90436-3 (doi:10.1016/0003-9861(58)90436-3) - DOI - DOI - PubMed
- Garfinkel D. 1958. Studies on pig liver microsomes. I. Enzymic and pigment composition of different microsomal fractions. Arch. Biochem. Biophys. 77, 493–50910.1016/0003-9861(58)90095-X (doi:10.1016/0003-9861(58)90095-X) - DOI - DOI - PubMed
- Omura T, Sato R. 1962. A new cytochrome in liver microsomes. J. Biol. Chem. 237, 1375–1376 - PubMed
- Conney AH. 1967. Pharmacological implications of microsomal enzyme induction. Pharmacol. Rev. 19, 317–366 - PubMed
- Gillette JR, Davis DC, Sasame HA. 1972. Cytochrome P-450 and its role in drug metabolism. Annu. Rev. Pharmacol. 12, 57–8410.1146/annurev.pa.12.040172.000421 (doi:10.1146/annurev.pa.12.040172.000421) - DOI - DOI - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical