Alternative titles; symbols
HGNC Approved Gene Symbol: CYP4A11
Cytogenetic location: 1p33 Genomic coordinates (GRCh38): 1:46,929,188-46,941,476 (from NCBI)
The human P450 enzymes encoded by CYP4 genes (see 124075) represent a distinct lineage of the P450 family. The CYP4A subfamily is involved in the metabolism of medium- and long-chain fatty acids (Cho et al., 2005).
Palmer et al. (1993) noted that mammalian CYP4A enzymes catalyze selective hydroxylation of a primary carbon-hydrogen bond in medium- and long-chain fatty acids. Palmer et al. (1993) cloned and characterized a CYP4A-encoding gene, designated CYP4AII, by screening a human kidney cDNA library using a rabbit CYP4A cDNA probe. By Northern and RNase protection analysis, they showed that the gene is expressed predominantly in kidney and somewhat in liver.
Bell et al. (1993) cloned human, mouse, and guinea pig CYP4A cDNAs, including human CYP4A11.
Kawashima et al. (1994) purified CYP4A fatty acid omega-hydroxylase, named P450HL-omega by them, from human liver. They cloned a CYP4A11 cDNA by screening a human liver cDNA library with a rabbit CYP4A5 cDNA. The CYP4A11 cDNA encodes a predicted 519-amino acid protein with a calculated molecular mass of 59.4 kD. The deduced sequence of residues 5 through 25 was identical to the N-terminal amino acid sequence of purified P450HL-omega, except for 1 undetermined residue. By Western blot analysis of transfected yeast microsomes, Kawashima et al. (1994) detected a specific protein with a mass of 52 kD, which is identical to that of purified P450HL-omega. Northern blot analysis showed that CYP4A11 is expressed as a 2.6-kb transcript.
Imaoka et al. (1993) cloned a variant cDNA of CYP4A11, termed CYP4A11v, from a human kidney cDNA library. The CYP4A11v cDNA contains a deletion of a single adenine residue, resulting in a frameshift and the production of a predicted 591-amino acid protein. Several differences in the 3-prime untranslated region of the CYP4A11v cDNA were also detected. Baculovirus-mediated expression of the CYP4A11v cDNA yielded an unstable protein that did not efficiently metabolize lauric acid.
Using PCR analysis, Savas et al. (2003) found that both CYP4A11 and CYP4A22 (615341) were expressed in 100 human liver tissue samples. Quantitative real-time PCR of 7 samples revealed that the enzymes were independently and variably expressed and that expression of CYP4A11 was significantly higher than that of CYP4A22.
Palmer et al. (1993) characterized the catalytic activity of expressed recombinant CYP4A11 on various fatty acids and prostaglandins and concluded that the enzyme is a fatty acid omega-hydroxylase with turnover numbers of 9.8, 2.2, and 0.55 per min for lauric, palmitic, and arachidonic acids, respectively.
Powell et al. (1996) demonstrated that CYP4A11 is the principal lauric acid omega-hydroxylase expressed in human liver.
Pikuleva and Waterman (2013) stated that CYP4A11 and CYP4A22 (615341) oxidize arachidonic acid to 20-hydroxyeicosatetraenoic acid in the endoplasmic reticulum of kidney tubules.
Savas et al. (2003) found that expression of CYP4A11 was undetectable in subconfluent human hepatoma HepG2 cells expressing human PPAR-alpha (PPARA; 170998) or a murine Ppar-alpha mutant with compromised ligand-dependent transactivation. However, upon attaining confluence, CYP4A11, but not CYP4A22, was upregulated in HepG2 cells expressing mutant Ppar-alpha following exposure to a Ppar-alpha agonist. Dexamethasone also induced CYP4A11, but not CYP4A22, expression, and dexamethasone-induced CYP4A11 was independent of PPAR-alpha.
Bell et al. (1993) mapped the human CYP4A11 gene to chromosome 1 by PCR of somatic cell hybrid DNAs.
By genomic sequence analysis, Nelson et al. (2004) mapped the CYP4A11 gene to a cluster of cytochrome P450 genes on chromosome 1p33.
Cho et al. (2005) presented 70 genetic variants of the CYP4A11 gene identified in 24 DNA samples from the Korean population. Sixty variants were intronic.
Association with Essential Hypertension
Gainer et al. (2005) screened the CYP4A11 gene and identified 9 variants with allelic frequencies greater than 1%, among them an 8590C-T transition in exon 11 resulting in a phe434-to-ser (F434S) substitution. Functional studies revealed that the ser434 replacement reduced by more than half the 20-HETE synthase activity of CYP4A11. In a population of 392 white individuals from Tennessee, Gainer et al. (2005) found that the age, BMI, and gender-adjusted odds ratio of hypertension (see 145500) attributable to the 8590C variant was 2.31 compared with the reference 8590TT genotype. In 1,538 individuals from the Framingham Heart Study, the adjusted odds ratio of hypertension associated with the 8590C variant was 1.23, and it was 1.33 when individuals with diabetes were excluded. The variant was not associated with hypertension in a population of 120 black individuals.
Nakagawa et al. (2006) created mice lacking Cyp4a10, an ortholog of human CYP4A11. Homozygous mutant mice developed normally and lacked obvious symptoms of disease or organ malformation, and disruption of the Cyp4a10 gene had little or no effect on kidney morphology or renal function before or after animal salt loading. Cyp4a10-null mice fed a low-salt diet were normotensive, but they became hypertensive when fed normal or high-salt diets. Hypertensive Cyp4a10-null mice had a dysfunctional kidney epithelial sodium channel (see SCNN1D; 601328) and became normotensive when administered amiloride, a selective inhibitor of this channel. Nakagawa et al. (2006) concluded that arachidonate monooxygenases alter renal sodium reabsorption and blood pressure and have a direct role in the gating activity of the kidney epithelial sodium channel.
Using transgenic mice expressing human CYP4A11, Savas et al. (2009) confirmed that expression of CYP4A11 was regulated by Ppar-alpha. Fasting or dietary administration of a PPAR-alpha agonist increased hepatic and renal CYP4A11 expression, and these responses were abrogated in Ppar-alpha -/- mice. Basal liver CYP4A11 levels were reduced differentially in Ppar-alpha -/- females (over 95%) and males (less than 50%). In Ppar-alpha -/- males, continuous infusion of growth hormone (see GH1, 139250) to mimic the female growth hormone pattern reduced expression of CYP4A11 to near female levels. Treatment with growth hormone decreased expression of CYP4A11 equally in both male and female wildtype mice.
The gene encoding this enzyme has also been called CYP4A2, which is presumably a derivation of CYP4AII.
Bell, D. R., Plant, N. J., Rider, C. G., Na, L., Brown, S., Ateitalla, I., Acharya, S. K., Davies, M. H., Elias, E., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Elcombe, C. R. Species-specific induction of cytochrome P-450 4A RNAs: PCR cloning of partial guinea-pig, human and mouse CYP4A cDNAs. Biochem. J. 294: 173-180, 1993. [PubMed: 8363569] [Full Text: https://doi.org/10.1042/bj2940173]
Cho, B. H., Park, B. L., Kim, L. H., Chung, H. S., Shin, H. D. Highly polymorphic human CYP4A11 gene. J. Hum. Genet. 50: 259-263, 2005. [PubMed: 15895287] [Full Text: https://doi.org/10.1007/s10038-005-0245-9]
Gainer, J. V., Bellamine, A., Dawson, E. P., Womble, K. E., Grant, S. W., Wang, Y., Cupples, L. A., Guo, C.-Y., Demissie, S., O'Donnell, C. J., Brown, N. J., Waterman, M. R., Capdevila, J. H. Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension. Circulation 111: 63-69, 2005. [PubMed: 15611369] [Full Text: https://doi.org/10.1161/01.CIR.0000151309.82473.59]
Imaoka, S., Ogawa, H., Kimura, S., Gonzalez, F. J. Complete cDNA sequence and cDNA-directed expression of CYP4A11, a fatty acid omega-hydroxylase expressed in human kidney. DNA Cell Biol. 12: 893-899, 1993. [PubMed: 8274222] [Full Text: https://doi.org/10.1089/dna.1993.12.893]
Kawashima, H., Kusunose, E., Kikuta, Y., Kinoshita, H., Tanaka, S., Yamamoto, S., Kishimoto, T., Kusunose, M. Purification and cDNA cloning of human liver CYP4A fatty acid omega-hydroxylase. J. Biochem. 116: 74-80, 1994. [PubMed: 7798189] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a124506]
Nakagawa, K., Holla, V. R., Wei, Y., Wang, W.-H., Gatica, A., Wei, S., Mei, S., Miller, C. M., Cha, D. R., Price, E., Jr., Zent, R., Pozzi, A., Breyer, M. D., Guan, Y., Falck, J. R., Waterman, M. R., Capdevila, J. H. Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel. J. Clin. Invest. 116: 1696-1702, 2006. [PubMed: 16691295] [Full Text: https://doi.org/10.1172/JCI27546]
Nelson, D. R., Zeldin, D. C., Hoffman, S. M. G., Maltais, L. J., Wain, H. M., Nebert, D. W. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 14: 1-18, 2004. [PubMed: 15128046] [Full Text: https://doi.org/10.1097/00008571-200401000-00001]
Palmer, C. N. A., Richardson, T. H., Griffin, K. J., Hsu, M.-H., Muerhoff, A. S., Clark, J. E., Johnson, E. F. Characterization of a cDNA encoding a human kidney, cytochrome P-450 4A fatty acid omega-hydroxylase and the cognate enzyme expressed in Escherichia coli. Biochim. Biophys. Acta 1172: 161-166, 1993. [PubMed: 7679927] [Full Text: https://doi.org/10.1016/0167-4781(93)90285-l]
Pikuleva, I. A., Waterman, M. R. Cytochromes P450: roles in diseases. J. Biol. Chem. 288: 17091-17098, 2013. [PubMed: 23632021] [Full Text: https://doi.org/10.1074/jbc.R112.431916]
Powell, P. K., Wolf, I., Lasker, J. M. Identification of CYP4A11 as the major lauric acid omega-hydroxylase in human liver microsomes. Arch. Biochem. Biophys. 335: 219-226, 1996. [PubMed: 8914854] [Full Text: https://doi.org/10.1006/abbi.1996.0501]
Savas, U., Hsu, M.-H., Johnson, E. F. Differential regulation of human CYP4A genes by peroxisome proliferators and dexamethasone Arch. Biochem. Biophys. 409: 212-220, 2003. [PubMed: 12464261] [Full Text: https://doi.org/10.1016/s0003-9861(02)00499-x]
Savas, U., Machemer, D. E. W., Hsu, M.-H., Gaynor, P., Lasker, J. M., Tukey, R. H., Johnson, E. F. Opposing roles of peroxisome proliferator-activated receptor alpha and growth hormone in the regulation of CYP4A11 expression in a transgenic mouse model. J. Biol. Chem. 284: 16541-16552, 2009. [PubMed: 19366684] [Full Text: https://doi.org/10.1074/jbc.M902074200]