Genetic studies CYP4A11 polymorphism Human CYP4A11 has 72.69% amino acid identity with murine cyp4a14 and 73.02% identity with murine cyp4a10 suggesting that it plays a role in humans similar to that of cyp4a14 and/or cyp4a10 in mice. The association of hypertension with defective CYP4A11 in humans as indicated below seems to parallel the hypertension associated with Cyp4a14
gene knockout in mice (see above section on genetic models). The
gene polymorphism rs1126742 variant of CYP4A11 switches thymidine to cytosine at nucleotide 8590 [T8590C] and leads to a phenylalanine-to-serine substitution at amino acid 434); this F434S variant has significantly reduced ability to ω-oxidize arachidonic acid to 20-HETE and has been associated with
essential hypertension in: 512 white males from Tennessee (
Odds ratio=2.31); 1538 males and females from the Framingham Heart Study (Odds ratio=1.23); males but not females in 732 black Americans with hypertensive renal disease participating in the African American Study of Kidney Disease; males in a sample of 507 individuals in Japan and in the third MONICA (MONitoring trends and determinants In Cardiovascular disease survey of 1397 individuals the homozygous C8590C genotype to the homozygous T8590T genotype with odds ratios of 3.31 for all subjects, 4.30 for males 2.93 for women); A study of 1501 participants recruited from the Tanno-Sobetsu Study found that the variant -845G in the promoter region of CYP411 (−845A is the predominant genotype) is associated with reduced transcription of CYP411 as well as with hypertension (odds ratio of homozygous and heterozygous -845G genotype versus homozygous -845A was 1.42); A
haplotype tagging
single-nucleotide polymorphism (SNP) (see
Tag SNP) variant of CYP4A11, C296T (cytosine to thymine at position 296), was associated with a significantly increased risk of
ischemic stroke (adjusted odds ratio of 1.50 in comparing homozygous and heterozygous C296T subjects to homozygous C286C subjects) in >2000 individuals taken from the Han Chinese population. The effect of the −296C>T single base pair substitution on baseline CYP411 transcriptional activity was not significant, suggesting that this polymorphism may not be the causal variant but instead may be in linkage disequilibrium with the causal variant. Regardless, this SNP may serve as a
genetic marker for large vessel disease stroke risk in this population.
CYP4F2 polymorphism The T allele at rs2108622, which has been designated as CYP4F2*3 in the Human CYP Allele Nomenclature Database by the Pharmacogene Variation Consortium, produces the CYP4F2 enzyme with methionine residue instead of valine at position 433 (the Val433Met variant), a
single-nucleotide polymorphism (1347C>T; NM_001082.5:c.1297G>A; p. Val433Met; rs2108622). This variant of the CYP4F2 enzyme has reduced capacity to metabolize arachidonic acid to 20-HETE but increased urinary excretion of 20-HETE. Studies found that:
a) among 161 hypertensive and 74 normotensive subjects in Australia, the incidence of the Val433Met variant was significantly increased in the hypertensive subjects;
c) among several hundred subjects in India, the variant was associated with hypertension; and
d) in comparing 249 patients with hypertension to 238 age-matched controls in Japan, the variant was not associated with hypertension. The maintenance of the lower blood pressure that followed diet-induced weight loss was more difficult for carriers of the Val433Met variant and may be related to increased arterial stiffness and increased 20-HETE synthesis. The Val433Met variant is also associated with an increased incidence of
cerebral infarction (i.e. ischemic stroke) in a study of 175 subjects with infarction compared to 246 control subjects in Japan, in 507 stroke patients compared to 487 age- and sex-matched 487 controls in India, and in male but not female patients in Sweden enrolled in the cardiovascular cohort of the Malmo Diet and Cancer Study. This platelet hyper-responsiveness to epinephrine, particularly if also exhibited to other platelet-aggregating agents, could contribute to cerebral and coronary infarctions.) The
Single-nucleotide polymorphism rs1558139 guanine to cytosine variant in an
intron of CYP4F2 is associated with essential hypertension in men only in a study of 249 hypertensive versus 238 age-matched controls in Japan.
CYP2U1 mutations A mutation (c.947A>T) in CYP2U1 has been associated with a small number of patients with
Hereditary spastic paraplegia in that it segregates with the disease at the homozygous state in two afflicted families. The mutation affects an amino acid (p.Asp316Val) highly conserved among CYP2U1
orthologs as well as other cytochrome P450 proteins; the p.Asp314Val mutation is located in the enzyme's functional domain, is predicted to be damaging to the enzyme's activity, and is associated with
mitochondria dysfunction. A second homozygous enzyme-disabling mutation has been identified in CYP2U1, c.1A>C/p.Met1?, that is associated with <1% of hereditary spastic paraplegia sufferers. While the role of 20-HETE in these mutations has not been established, the reduction in 20-HETE production and thereby 20-HETE's activation of the TRPV1 receptor in nerve tissues, it is hypothesized, may contribute to the disease. Isoliquiritigenin also inhibits the in vivo lung metastasis of MDA-MB-231 cell transplants while concurrently decreasing the tumor's levels of 20-HETE. Messenger RNAs not only for CYP4Z2 but also for CYP4A11, CYP4A22, CYP4F2, and CYP4F3 are more highly expressed in samples of human breast cancer tumors compared to normal breast tissue. The
Three prime untranslated regions (3'UTRs) of the CYP4Z1 gene and its
Pseudogene, CYP4Z2P, share several
miRNA-binding sites, including those for miR-211, miR-125a-3p, miR-197, miR-1226, and miR-204'. Since these miRNA's reduce the translation of CYP4Z1, the expression of CYP4Z2P can bind these miRNAs to reduce their interference with CYP4Z1 and thereby increase the production of CYP4Z1 protein and perhaps 20-HETE; indeed, force expression of these 3'UTRs promoted in vitro tumor angiogenesis in breast cancer cells partly via miRNA-dependent activation of the
phosphoinositide 3-kinase-
MAPK/ERK pathway and thereby stimulating the production of vascular endothelium growth factor and possibly other endothelium growth factors. A selective inhibitor of 20-HETE synthesis and a 20-HETE antagonist reduced the growth of two human kidney cancer
786-O and
769-P cell lines in culture; the 20-HETE antagonist also inhibited the growth of 786-O cells transplanted into athymic nude mice. Messenger RNAs for CYP4A11, CYP4A22, CYP4F2, and/or CYP4F3 are more highly expressed in ovary, colon, thyroid, lung, ovary, cancers compared to their normal tissue counterparts; in ovarian cancer, this higher expression is associated with an increased level of CYP4F2 protein expression and an increased ability to metabolize arachidonic acid to 20-HETE. Ovarian cancers also overexpress CYP4Z1 mRNA protein; this overexpression is associated with a poorer disease outcome. While these studies suggest that CYP4A11, CYP4A22, CYP4F2, and/or CYP4F3 produce 20-HETE which in turn promotes the growth of the cited cancers in model systems and therefore may do so in the human cancers, this suggestion clearly needs much further study. For example, an inhibitor of 20-HETE production blocks the growth of human brain
U251 glioma cells in culture; since these cells could not be shown to produce 20-HETE, it was proposed that some other metabolite may by the inhibitor's targeted cytochrome enzymes was responsible for maintaining these cells growth. It is also possible that any such inhibitor has off-target effects that are responsible for its actions.
Platelet aggregation 20-HETE inhibits the aggregation of human platelets by competing with arachidonic acid for the enzymes that produce prostaglandin H2 and thromboxane A2. These products are formed in response to platelet stimulation and then act through the
thromboxane receptor to mediate and/or promote the ensuing platelet aggregation response to most stimuli. The platelets metabolize 20-HETE to the 20-hydroxy analogs of prostaglandin H2 and thromboxane A2, products that are essentially inactive in platelets, while consequently form less of the arachidonic acid-derived prostaglandin and thromboxane products. In addition, 20-HETE itself blocks prostaglandin and thromboxane metabolites from interacting with the thromboxane receptor. == References ==