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.

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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.

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Figures

Figure 1.

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.

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.

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.

Figure 4.

Simplified scheme illustrating the P450 enzymes involved in steroidogenesis. CYB5, cytochrome b5; DHEA, dehydroepiandrosterone.

Figure 5.

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.

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