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Gene Review

CYP4B1  -  cytochrome P450, family 4, subfamily B,...

Homo sapiens

Synonyms: CYPIVB1, Cytochrome P450 4B1, Cytochrome P450-HP, P-450HP
 
 
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Disease relevance of CYP4B1

  • Given the relatively high frequency and the functional consequences of the CYP4B1*2 allele, associations between CYP4B1 polymorphism and certain pathological processes should be considered [1].
  • The most sensitive CYP4B1-expressing glioma clone, 9L4B1-60, displayed an LD50 of 2.5 microM for 2-AA and 4-IM after 48 h of prodrug incubation, whereas 20 times higher prodrug concentrations did not cause any significant toxicity to control cells [2].
  • Toxicity of these two prodrugs was evaluated in culture in parental and genetically modified rodent (9L) and human (U87) glioma cell lines stably expressing CYP4B1, and in vivo in a subcutaneous 9L tumor model in nude mice [2].
  • In a search for more selective and more potent bioactivating enzymes for gene therapy of malignant brain tumors, the toxicity-generating capacity of the rabbit cytochrome P450 isozyme CYP4B1 was investigated [2].
  • Unexpectedly, recombinant CYP4B1 from insect cells and Escherichia coli also bound their heme covalently at the C-8 methyl position [3].
 

High impact information on CYP4B1

  • The amounts of each of the three mRNAs varied considerably between patients, but analysis of frequency distribution of the levels of CYP2B7 and CYP4B1 mRNAs did not present evidence for genetic polymorphism as a possible source of the observed interindividual variability [4].
  • Quantification of CYP2B7, CYP4B1, and CYPOR messenger RNAs in normal human lung and lung tumors [4].
  • CYP2F1 and CYP4B1, two enzymes that are expressed in lung, display only modest 3- and 2-fold respective increased abilities to metabolically activate 4-ipomeanol [5].
  • Other forms present in full-term placenta include CYP4B1 and CYP19 (steroid aromatase), which also contribute to the oxidation of some xenobiotics [6].
  • In both CYP4B1-expressing cells and co-cultured control cells, prodrug bioactivation was associated with DNA fragmentation, as assayed by fluorescent TUNEL assays and by annexin V staining [2].
 

Chemical compound and disease context of CYP4B1

 

Biological context of CYP4B1

  • This cDNA sequence deduced amino acid sequence encodes a P450 protein having a conserved region of the CYP4 family exhibiting 44-45% amino acid identity to rat CYP4A subfamily members, 43% to human CYP4B1, 35 and 32% to insect CYP4C1 and CYP4D1, respectively [9].
  • Although gene expression levels within each subfamily were closely correlated within PBL and within the liver, a clear correlation of gene expression levels between PBL and liver tissues was found only for CYP4B1 [10].
  • These data show (i) that E310 serves as the site of covalent attachment of heme to the protein backbone of rabbit CYP4B1; (ii) this I-helix glutamate residue influences substrate orientation in the active site of CYP4B1; and (iii) the mechanism of covalent heme attachment most likely involves a carbocation species located on the porphyrin [11].
  • The bioactivation capabilities of rabbit CYP4B1 have also attracted attention in the cancer community and form the basis of a potential therapeutic strategy involving prodrug activation by the CYP4B1 transgene [12].
  • Also, many CYP4B1 enzymes covalently bind their heme, a posttranslational modification unique to the CYP4 family of P450s, but common to the mammalian peroxidases [12].
 

Anatomical context of CYP4B1

 

Associations of CYP4B1 with chemical compounds

 

Regulatory relationships of CYP4B1

 

Other interactions of CYP4B1

  • CYP1B1 was consistently expressed and CYP3A5 and CYP4B1 were expressed in a majority of the samples tested [21].
  • This pathway is primarily mediated by the phase-I enzymes CYP1A1, CYP1A2 and CYP4B1 [13].
  • In particular, transcripts of CYP1B1 and CYP4B1 are present, coding for enzymes which are active in the metabolism of polycyclic aromatic hydrocarbons and arylamines, respectively [14].
  • In addition, treatment of CYP4B1, CYP4F3, and CYP4A5/7 with strong base generated a new, chromatographically distinct, polar heme species with a mass of 632.3 amu rather than 616.2 amu [17].
  • Moreover, heme was not substantially removed from CYP4B1 under electrospray or electrophoresis conditions that readily release the prosthetic group from other non-CYP4 P450 isoforms [17].
 

Analytical, diagnostic and therapeutic context of CYP4B1

References

  1. Genetic polymorphism of the human cytochrome P450 CYP4B1: evidence for a non-functional allelic variant. Lo-Guidice, J.M., Allorge, D., Cauffiez, C., Chevalier, D., Lafitte, J.J., Lhermitte, M., Broly, F. Pharmacogenetics (2002) [Pubmed]
  2. New prodrug activation gene therapy for cancer using cytochrome P450 4B1 and 2-aminoanthracene/4-ipomeanol. Rainov, N.G., Dobberstein, K.U., Sena-Esteves, M., Herrlinger, U., Kramm, C.M., Philpot, R.M., Hilton, J., Chiocca, E.A., Breakefield, X.O. Hum. Gene Ther. (1998) [Pubmed]
  3. Sites of covalent attachment of CYP4 enzymes to heme: evidence for microheterogeneity of P450 heme orientation. Baer, B.R., Schuman, J.T., Campbell, A.P., Cheesman, M.J., Nakano, M., Moguilevsky, N., Kunze, K.L., Rettie, A.E. Biochemistry (2005) [Pubmed]
  4. Quantification of CYP2B7, CYP4B1, and CYPOR messenger RNAs in normal human lung and lung tumors. Czerwinski, M., McLemore, T.L., Gelboin, H.V., Gonzalez, F.J. Cancer Res. (1994) [Pubmed]
  5. Metabolic activation of 4-ipomeanol by complementary DNA-expressed human cytochromes P-450: evidence for species-specific metabolism. Czerwinski, M., McLemore, T.L., Philpot, R.M., Nhamburo, P.T., Korzekwa, K., Gelboin, H.V., Gonzalez, F.J. Cancer Res. (1991) [Pubmed]
  6. Xenobiotic-metabolizing cytochrome P450 enzymes in the human feto-placental unit: role in intrauterine toxicity. Hakkola, J., Pelkonen, O., Pasanen, M., Raunio, H. Crit. Rev. Toxicol. (1998) [Pubmed]
  7. Rabbit cytochrome P450 4B1: A novel prodrug activating gene for pharmacogene therapy of hepatocellular carcinoma. Mohr, L., Rainov, N.G., Mohr, U.G., Wands, J.R. Cancer Gene Ther. (2000) [Pubmed]
  8. Thiamine transporter gene expression and exogenous thiamine modulate the expression of genes involved in drug and prostaglandin metabolism in breast cancer cells. Liu, S., Stromberg, A., Tai, H.H., Moscow, J.A. Mol. Cancer Res. (2004) [Pubmed]
  9. Identification of a new P450 subfamily, CYP4F1, expressed in rat hepatic tumors. Chen, L., Hardwick, J.P. Arch. Biochem. Biophys. (1993) [Pubmed]
  10. Cytochrome p450 gene expression levels in peripheral blood mononuclear cells in comparison with the liver. Furukawa, M., Nishimura, M., Ogino, D., Chiba, R., Ikai, I., Ueda, N., Naito, S., Kuribayashi, S., Moustafa, M.A., Uchida, T., Sawada, H., Kamataki, T., Funae, Y., Fukumoto, M. Cancer Sci. (2004) [Pubmed]
  11. Covalent heme binding to CYP4B1 via Glu310 and a carbocation porphyrin intermediate. Zheng, Y.M., Baer, B.R., Kneller, M.B., Henne, K.R., Kunze, K.L., Rettie, A.E. Biochemistry (2003) [Pubmed]
  12. CYP4B1: an enigmatic P450 at the interface between xenobiotic and endobiotic metabolism. Baer, B.R., Rettie, A.E. Drug Metab. Rev. (2006) [Pubmed]
  13. The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: functional and localization studies. Windmill, K.F., McKinnon, R.A., Zhu, X., Gaedigk, A., Grant, D.M., McManus, M.E. Mutat. Res. (1997) [Pubmed]
  14. Expression of cytochrome P450 enzymes CYP1A1, CYP1B1, CYP2E1 and CYP4B1 in cultured transitional cells from specimens of the human urinary tract and from urinary sediments. Roos, P.H., Belik, R., Föllmann, W., Degen, G.H., Knopf, H.J., Bolt, H.M., Golka, K. Arch. Toxicol. (2006) [Pubmed]
  15. Species-specific expression of CYP4B1 in rabbit and human gastrointestinal tissues. McKinnon, R.A., Burgess, W.M., Gonzalez, F.J., Gasser, R., McManus, M.E. Pharmacogenetics (1994) [Pubmed]
  16. CYP4B1 is a possible risk factor for bladder cancer in humans. Imaoka, S., Yoneda, Y., Sugimoto, T., Hiroi, T., Yamamoto, K., Nakatani, T., Funae, Y. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  17. Covalent linkage of prosthetic heme to CYP4 family P450 enzymes. Henne, K.R., Kunze, K.L., Zheng, Y.M., Christmas, P., Soberman, R.J., Rettie, A.E. Biochemistry (2001) [Pubmed]
  18. Bioactivation of 4-ipomeanol by CYP4B1: adduct characterization and evidence for an enedial intermediate. Baer, B.R., Rettie, A.E., Henne, K.R. Chem. Res. Toxicol. (2005) [Pubmed]
  19. Identification of a meander region proline residue critical for heme binding to cytochrome P450: implications for the catalytic function of human CYP4B1. Zheng, Y.M., Fisher, M.B., Yokotani, N., Fujii-Kuriyama, Y., Rettie, A.E. Biochemistry (1998) [Pubmed]
  20. A transgenic mouse expressing human CYP4B1 in the liver. Imaoka, S., Hayashi, K., Hiroi, T., Yabusaki, Y., Kamataki, T., Funae, Y. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  21. Detection of cytochrome P450 mRNA transcripts in prostate samples by RT-PCR. Finnström, N., Bjelfman, C., Söderström, T.G., Smith, G., Egevad, L., Norlén, B.J., Wolf, C.R., Rane, A. Eur. J. Clin. Invest. (2001) [Pubmed]
  22. Molecular mechanisms regulating human CYP4B1 lung-selective expression. Poch, M.T., Cutler, N.S., Yost, G.S., Hines, R.N. Drug Metab. Dispos. (2005) [Pubmed]
 
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