Philos Trans R Soc Lond B Biol Sci 368(1612): 20120431

Human cytochromes P450 in health and disease

^{Department of Environmental Health, Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA}

^{Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Uppsala 751 23, Sweden}

^{Department of Pediatrics, Division of Endocrinology, University of California, San Francisco, CA 94143-1346, USA}

e-mail: ude.cu@treben.nad

One contribution of 9 to a Theme Issue ‘Cytochrome P450 and its impact on planet Earth’.

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.

Keywords: eicosanoids, drug-metabolizing enzymes, steroidogenesis, vitamin D biosynthesis, retinoids, bile acids

Abstract

^{EETs can be converted quickly to DHETEs and to ω- and ω-1 alcohols. HPETEs can be reduced to HETEs and converted to hepoxilins. Thus, a critical life function attributed to EETs or to HPETEs might actually reflect the activity of one or more of their downstream products; the same can be said for many of the other categories of eicosanoids (reviewed, with detailed references, in [}40]).

Acknowledgements

We thank our colleagues for valuable suggestions and critical readings of this manuscript. We are grateful to Marian L. Miller, Prof. Emerita, for her help with graphics. This work was supported, in part, by the following grants: NIH P30 ES006096 (D.W.N.), the Swedish Research Council-Medicine (K.W.) and NIH R01 DK037922 and R01 GM037020 (W.L.M.).

Acknowledgements

Glossary

1,25(OH)₂D: 1α,25-dihydroxy vitamin D
25(OH)D: 25-hydroxy vitamin D
ABS: Antley–Bixler syndrome
ALDH1A1, 1A2 and1A3: retinaldehyde dehydrogenases
ALOXs: arachidonate lipoxygenases
CAH: congenital adrenal hyperplasia
CNS: central nervous system
CTX: cerebrotendinous xanthomatosis
CYB5: cytochrome b₅
CYP: cytochrome P450 (CYP, human genes; Cyp, mouse genes)
DHETEs: dihydroxyeicosatrienoic acids
EDCs: endocrine-disrupting chemicals
EETs: epoxyeicosatrienoic acids
ER: endoplasmic reticulum
FAD: flavin adenine dinucleotide
FDX: ferrodoxin
FDXR: ferrodoxin reductase
FMN: flavin mononucleotide
FXR: farnesoid X receptor
GD: gestational day
HETEs: hydroxyeicosatetraenoic acids
HMG-CoA: hydroxymethylglutaryl coenzyme A
HPETEs: hydroperoxyeicosatetraenoic acids
HSP: hereditary spastic periplegia
LXR: liver X receptor
PDGF: platelet–derived growth factor
PG: prostaglandin (I₂, E₂, D₂, F_2α)
PGI₂: prostacyclin
PK: pharmacokinetic
POR: P450 oxidoreductase (Por, mouse gene encoding POR)
PTGIS gene (human): encodes prostacyclin synthase (also called CYP8A1)
PTGS1 and 2: cyclooxygenase-1 and -2 (COX1, COX2)
PXR: prostane X receptor
RA: retinoic acid
SNPs: single-nucleotide polymorphisms
StAR: steroidogenic acute regulatory protein
T gene (mouse): encodes brachyury transcription factor
Tbx1 gene (mouse): encodes T-box 1 transcription factor
TBXA₂: thromboxane A₂
TBXAS1 gene (human): encodes thromboxane synthase (also called CYP5A1)
Tyr gene (mouse): encodes tyrosinase
UM: ultra-metabolizer phenotype
VDR: vitamin D receptor
Wnt3a gene (Drosophila homologue in mouse): encodes Wingless-Int proteins involved in determination of left-right and dorsal-ventral axes

Glossary

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