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Gene Section
Review
CYP4B1 (cytochrome P450, family 4, subfamily B,
polypeptide 1)
Edward J Kelly, Vladimir Yarov-Yarovoy, Allan E Rettie
Department of Pharmaceutics, University of Washington, Seattle, USA (EJK), Department of Physiology
and Membrane Biology, Department of Biochemistry and Molecular Medicine, School of Medicine,
University of California, Davis, USA (VYY), Department of Medicinal Chemistry, University of
Washington, Seattle, USA (AER)
Published in Atlas Database: February 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/CYP4B1ID40253ch1p33.html
DOI: 10.4267/2042/47413
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Transcription
Identity
Two major transcripts are known to derive from
alternative
splicing
(NM_000779.3,
NM_001099772.1). Isoform 1 encodes a 511 amino
acid protein, while isoform 2 encodes a 512 amino acid
protein with a Ser206 insertion.
It should be noted that this is a complicated locus with
many other possibilities for alternative splicing.
Other names: CYPIVB1, P-450HP
HGNC (Hugo): CYP4B1
Location: 1p33
DNA/RNA
Description
Pseudogene
The CYP4B1 gene has 12 exons resulting in an open
reading frame of 1533 bp (isoform 1). The CYP4B1
locus is depicted in figure 1 (NCBI).
No pseudogene is known for CYP4B1.
Figure 1. Localization of the CYP4B1 locus to chromosome 1p33 and sites (exons 5, 8 and 9) of polymorphic variants that describe the 7
allelic variants of CYP4B1 (see table 1 for details).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
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CYP4B1 (cytochrome P450, family 4, subfamily B, polypeptide 1)
Kelly EJ, et al.
the core I-helix forms a covalent, ester linkage at the C5 methyl group of the heme (Henne et al., 2001).
The function of the unusual modification has not been
established, although it may serve to rigidify the
enzyme's active site and modulate the substrate
selectivity of CYP4B1.
The CYP4B1 enzyme is highly conserved across
species - see figure 2 below that also highlights the
position of the cysteinyl ligand and the I-helix
glutamate.
Protein
Note
CYP4B1 belongs to the mammalian CYP4 enzyme
family that also includes CYP4A, 4F and the recently
discovered CYP 4V, 4X and 4Z sub-families (Rettie
and Kelly, 2008). P450 enzymes usually function as
monooxygenases in that they incorporate one atom of
molecular oxygen into their substrates and reduce the
other to water.
CYP4 enzymes typically catalyze fatty acid ωhydroxylase reactions.
Expression
CYP4B1 mRNA and/or protein are found typically at
the highest levels in lung and airway tissue.
Liver levels of the enzyme are usually much lower, but
inducible by phenobarbital.
Expression of the enzyme in mouse kidney is regulated
by androgens. CYP4B1 is highly expressed in several
cancer types, including colon, adrenal gland, lung and
gastric cancers.
Description
Structurally, P450 enzymes all share a similar fold
featuring a β-sheet rich N-terminus and an α-helix rich
C-terminus.
The hydrophobic N-terminus of eukaryotic P450s
functions as membrane anchor, whereas the C-terminal
region houses the cysteinyl heme (iron protoporphyrin
IX) cofactor that binds and activates molecular oxygen.
Many CYP4 enzymes, including CYP4B1, possess a
unique post-translational modification at the heme
active center, wherein a conserved glutamate residue in
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
Localisation
CYP4B1 is located in the ER membrane, although one
report suggests that the rat enzyme may be a secreted
protein in respiratory mucosa (Genter et al., 2006).
454
CYP4B1 (cytochrome P450, family 4, subfamily B, polypeptide 1)
Kelly EJ, et al.
Figure 2. Multiple sequence alignment of vertebrate CYP4B proteins. The covalently heme-linked glutamate residue is indicated in bold
italics and the heme-coordinating cysteinyl ligand depicted in bold underline. The Pro>Ser substitution at position 427 in human CYP4B1
is depicted in italics. Alignments determined using the ClustalW2 multiple sequence alignment program available online at EMBL-EBI.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
455
CYP4B1 (cytochrome P450, family 4, subfamily B, polypeptide 1)
Kelly EJ, et al.
liver expression and therefore has been suggested as a
surrogate marker for hepatic bioactivation of
environmental pro-toxins (Furukawa et al., 2004). An
increased risk of bladder cancer (OR of 1.03-2.95) has
been reported in Japanese patients carrying the
CYP4B1*2 allele (Sasaki et al., 2008). One potential
explanation could be that CYP4B1 is known to play a
role in aromatic amine bioactivation (Windmill et al.,
1997) and these compounds are known bladder
carcinogens and present in cooked meats (Jägerstad and
Skog, 2005) and cigarette smoke (Smith et al., 1997),
among other sources. However, no association was
found between lung cancer risk and CYP4B1*1-*7
polymorphisms in Japanese (Tamaki et al., 2011).
Mutations
Note
Seven alleles (CYP4B1*1-*7) are listed at
http://www.cypalleles.ki.se/cyp4b1.htm
and
summarized in table 1 below. The CYP4B1*1 allele is
described by a composition of the major alleles shown
in table 1. CYP4B1*2 contains the haplotype of the 294
frameshift along with M331I, R340C and R375C.
CYP4B1*7 is the same haplotype minus the R375C
variant. CYP4B1*3/4/5 are described by the R173W,
S322G and M331I polymorphisms, respectively.
CYP4B1*6 is R173W in combination with V345I.
Nucleotide
Change,
cDNA
position
517C>T
881_882∆AT
964A>G
993G>A
1018C>T
1033G>A
1123C>T
Protein
Coding
Sequence
Change
R173W
294
frameshift
(STOP)
S322G
M331I
R340C
V345I
R375C
Heterozygosity1
Angiogenesis
Note
Studies conducted in a rabbit model of corneal wound
healing have implicated that CYP4B1 may play a role
in production of inflammatory eicosanoids and corneal
neovascularization (Mastyugin et al., 2001).
These observations are corroborated by findings in
mice, whereby heme oxygenase-I induction attenuates
corneal inflammation and is associated with a lack of
CYP4B1 induction (and eicosanoid production) (Patil
et al., 2008).
Conversely, retinoic acid (RA) has been shown to
increase CYP4B1 gene expression in ocular organ
cultures, resulting in increased metabolism of
arachidonic acid to 12-HETE and 12-HETrE (Ashkar et
al., 2004). These effects were shown to be mediated, at
least in part, by transcriptional regulation of the rabbit
CYP4B1 promoter, which contains several RAR/RXR
binding motifs (Ashkar et al., 2004). While RA is
typically associated with corneal wound healing, the
induction of CYP4B1 by RA suggests it may also have
a pro-inflammatory role in wound healing. This is
supported by the observation that systemic treatment
with 13-cis-retinoic acid (Accutane™) for cystic acne
is associated with conjunctivitis, eyelid inflammation
and keratitis, along with other ocular effects (Lebowitz
and Berson, 1988).
Further evidence that CYP4B1 is important in ocular
inflammation,
eicosanoid
production
and
neovascularization is shown in a study by Seta et al.,
using in vivo siRNA targeting of CYP4B1 in a rabbit
model of corneal wound healing.
It was found that down-regulation of CYP4B1 inhibited
production of 12- HETrE and VEGF in addition to
decreasing neovascularization (Seta et al., 2007).
0.28
0.34
0.02
0.40
0.22
ND
0.26
Table 1. CYP4B1 polymorphic variants including nucleotide
changes and effect on protein coding sequences. 1 The values
for heterozygosity of the minor alleles are taken from NCBI. ND:
not determined.
Recent exome sequencing has revealed considerable
additional polymorphism (>75 total SNPs) in the
human CYP4B1 gene (search at Exome Variant
Server).
Implicated in
Various cancers
Note
CYP4B1 mRNA and/or protein are highly expressed in
some cancer types. In particular Imaoka et al.
demonstrated increased CYP4B1 in bladder tumor
tissue at both the mRNA and protein level (Imaoka et
al., 2000). This finding is also consistent with rodent
studies demonstrating localization of CYP4B1 in
mouse and rat bladder tissue (Imaoka et al., 1997;
Imaoka et al., 2001). However, Czerwinski et al.
observed down regulation of CYP4B1 mRNA in lung
tumors relative to normal lung (Czerwinski et al.,
1994). With breast cancer, there does not appear to be
any difference in expression of CYP4B1 when
comparing tumor tissue with surrounding healthy
tissue, but these studies did not use disease-free
subjects as a comparator (Iscan et al., 2001). Relatively
high expression of constitutive CYP4B1
mRNA has been found in human urothelial cells (Roos
et al., 2006). Peripheral blood mononuclear cell
CYP4B1 mRNA expression correlated with human
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
Colitis
Note
Several recent studies have implicated a potential role
for CYP4B1 in inflammatory bowel disease (IBD). In a
mouse model of dextran sodium sulfate (DSS)-induced
colitis, Ye et al. found that caffeic acid treatment
decreased disease severity and this was associated with
increased expression of Cyp4b1 in affected tissues (Ye
456
CYP4B1 (cytochrome P450, family 4, subfamily B, polypeptide 1)
Kelly EJ, et al.
Zheng YM, Fisher MB, Yokotani N, Fujii-Kuriyama Y, Rettie
AE. Identification of a meander region proline residue critical
for heme binding to cytochrome P450: implications for the
catalytic function of human CYP4B1. Biochemistry. 1998 Sep
15;37(37):12847-51
et al., 2009). In a subsequent study looking at the role
of caffeic acid bioavailability in this model, they found
that mice treated with DSS alone had lower colonic
Cyp4b1 expression when compared to DSS plus caffeic
acid treated mice (Ye et al., 2011). In a different mouse
model of IBD, Liu et al. also found evidence that
Cyp4b1 gene expression is altered in this disease state
(Liu et al., 2009). It was found that IBD induced by
infection with Helicobacter bilis resulted in changes in
mucosal gene expression patterns. Using microarray
analysis, it was found that H. bilis infection resulted in
decreased expression of Cyp4b1. These authors also
examined mice with IBD induced by DSS and, akin to
Liu et al., found decreased expression of Cyp4b1 in
diseased tissue. These findings suggest an antiinflammatory role for CYP4B1 in IBD, but these
preclinical studies must be weighed against what is
known about gastrointestinal expression of CYP4B1
and human IBD. While rodents and rabbits and other
species are known to expression CYP4B1 in the gut,
there are species-specific differences, with humans
expressing little CYP4B1 in this tissue (McKinnon et
al., 1994). Whether the CYP4B1 gene plays any role in
IBD is unclear, particularly in light of the functionality
of the Pro427Ser human protein (Zheng et al., 1998).
Finally, in considering risk of developing IBD, a
genome wide association study by The Wellcome Trust
examining 2000 cases of Crohn's with 3000 controls,
found no significant association between CYP4B1
genetic variants and disease incidence (Wellcome Trust
Case Control Consortium, 2007).
Imaoka S, Yoneda Y, Sugimoto T, Hiroi T, Yamamoto K,
Nakatani T, Funae Y. CYP4B1 is a possible risk factor for
bladder cancer in humans. Biochem Biophys Res Commun.
2000 Nov 2;277(3):776-80
Henne KR, Kunze KL, Zheng YM, Christmas P, Soberman RJ,
Rettie AE. Covalent linkage of prosthetic heme to CYP4 family
P450 enzymes. Biochemistry. 2001 Oct 30;40(43):12925-31
Imaoka S, Yoneda Y, Sugimoto T, Ikemoto S, Hiroi T,
Yamamoto K, Nakatani T, Funae Y. Androgen regulation of
CYP4B1 responsible for mutagenic activation of bladder
carcinogens in the rat bladder: detection of CYP4B1 mRNA by
competitive reverse transcription-polymerase chain reaction.
Cancer Lett. 2001 May 26;166(2):119-23
Iscan M, Klaavuniemi T, Coban T, Kapucuoglu N, Pelkonen O,
Raunio H. The expression of cytochrome P450 enzymes in
human breast tumours and normal breast tissue. Breast
Cancer Res Treat. 2001 Nov;70(1):47-54
Mastyugin V, Mosaed S, Bonazzi A, Dunn MW, Schwartzman
ML. Corneal epithelial VEGF and cytochrome P450 4B1
expression in a rabbit model of closed eye contact lens wear.
Curr Eye Res. 2001 Jul;23(1):1-10
Ashkar S, Mesentsev A, Zhang WX, Mastyugin V, Dunn MW,
Laniado-Schwartzman M. Retinoic acid induces corneal
epithelial CYP4B1 gene expression and stimulates the
synthesis of inflammatory 12-hydroxyeicosanoids. J Ocul
Pharmacol Ther. 2004 Feb;20(1):65-74
Furukawa M, Nishimura M, Ogino D, Chiba R, Ikai I, Ueda N,
Naito S, Kuribayashi S, Moustafa MA, Uchida T, Sawada H,
Kamataki T, Funae Y, Fukumoto M. Cytochrome p450 gene
expression levels in peripheral blood mononuclear cells in
comparison with the liver. Cancer Sci. 2004 Jun;95(6):520-9
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Kelly EJ, Yarov-Yarovoy V, Rettie AE. CYP4B1 (cytochrome
P450, family 4, subfamily B, polypeptide 1). Atlas Genet
Cytogenet Oncol Haematol. 2012; 16(7):453-458.
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