Carbonyl reductase is one of several monomeric, NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds. This enzyme is widely distributed in human tissues. Another carbonyl reductase gene, CBR3, lies close to this gene on chromosome 21q22.12.[5] CBR1 metabolizes many toxic environmental quinones and pharmacological relevant substrates such as the anticancer doxorubicin.[8] Several studies have shown that CBR1 plays a protective role in oxidative stress, neurodegeneration, and apoptosis.[9] In addition, CBR1 inactivates lipid aldehydes during oxidative stress in cells. Therefore, CBR1 may play a beneficial role in protecting against cellular damage resulting from oxidative stress.[10]
Polymorphisms
Up-to-date two non-synonymous polymorphisms on CBR1 have been identified. The CBR1 V88I polymorphism encodes for a valine-to-isoleucine substitution at position 88 of the aminoacid chain. In vitro studies with recombinant proteins indicate that the CBR1 V88 isoform has a higher Vmax towards the substrates menadione (vitamin K3) and daunorubicin.[11] Recent studies in human liver cytosols show that an untranslated polymorphism on the 3'UTR region of the CBR1 gene (rs9024)[12] is associated with higher levels of the cardiotoxic metabolite doxorubicinol.[13]
CBR1 has been reported to relate to tumor progression.[16] Suppression of CBR1 expression was associated with poor prognosis in uterine endometrial cancer and uterine cervical squamous cell carcinoma.[16] Previous studies showed that decreased CBR1 expression is associated with lymph node metastasis and poor prognosis in ovarian cancer, and induction of CBR1 expression in ovarian tumors leads to a spontaneous decrease in tumor size.[17]
Recent study demonstrates that CBR1 attenuates apoptosis and promotes cell survival in pancreatic β cell lines under glucotoxic and glucolipotoxic conditions via reducing ROS generation. Their data demonstrates that CBR1 expression level and enzyme activity are decreased in pancreatic islets isolated from db/db mice, an animal model of type 2 diabetes. These results suggest that CBR1 may play a role in protecting pancreatic β-cells against oxidative stress under glucotoxic or glucolipotoxic conditions, and its reduced expression or activity may contribute to β-cell dysfunction in db/db mice or human type 2 diabetes.[14]
In addition, CBR1 may play a critical role in prostaglandin F2α (PGF2α) synthesis in human amnionfibroblasts, and cortisol promotes the conversion of PGE2 into PGF2α via glucocorticoid receptor (GR)-mediated induction of CBR1 in human amnionfibroblasts. This stimulatory effect of cortisol on CBR1 expression may partly explain the concurrent increases of cortisol and PGF2α in human amnion tissue with labor, and these findings may account for the increased production of PGF2α in the fetal membranes prior to the onset of labor.[18]
↑ Nelson SH, Grunebaum H (April 1971). "A follow-up study of wrist slashers". The American Journal of Psychiatry. 127 (10): 1345–9. doi:10.1176/ajp.127.10.1345. PMID5549925.
Inazu N, Ruepp B, Wirth H, Wermuth B (Mar 1992). "Carbonyl reductase from human testis: purification and comparison with carbonyl reductase from human brain and rat testis". Biochimica et Biophysica Acta (BBA) - General Subjects. 1116 (1): 50–6. doi:10.1016/0304-4165(92)90127-g. PMID1540623.
Forrest GL, Akman S, Doroshow J, Rivera H, Kaplan WD (Oct 1991). "Genomic sequence and expression of a cloned human carbonyl reductase gene with daunorubicin reductase activity". Molecular Pharmacology. 40 (4): 502–7. PMID1921984.
Forrest GL, Akman S, Krutzik S, Paxton RJ, Sparkes RS, Doroshow J, Felsted RL, Glover CJ, Mohandas T, Bachur NR (Apr 1990). "Induction of a human carbonyl reductase gene located on chromosome 21". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1048 (2–3): 149–55. doi:10.1016/0167-4781(90)90050-c. PMID2182121.
Wermuth B, Platts KL, Seidel A, Oesch F (Apr 1986). "Carbonyl reductase provides the enzymatic basis of quinone detoxication in man". Biochemical Pharmacology. 35 (8): 1277–82. doi:10.1016/0006-2952(86)90271-6. PMID3083821.
Wermuth B, Mäder-Heinemann G, Ernst E (Mar 1995). "Cloning and expression of carbonyl reductase from rat testis". European Journal of Biochemistry. 228 (2): 473–9. doi:10.1111/j.1432-1033.1995.tb20286.x. PMID7705364.
Lemieux N, Malfoy B, Forrest GL (Jan 1993). "Human carbonyl reductase (CBR) localized to band 21q22.1 by high-resolution fluorescence in situ hybridization displays gene dosage effects in trisomy 21 cells". Genomics. 15 (1): 169–72. doi:10.1006/geno.1993.1024. PMID8432528.
Watanabe K, Sugawara C, Ono A, Fukuzumi Y, Itakura S, Yamazaki M, Tashiro H, Osoegawa K, Soeda E, Nomura T (Aug 1998). "Mapping of a novel human carbonyl reductase, CBR3, and ribosomal pseudogenes to human chromosome 21q22.2". Genomics. 52 (1): 95–100. doi:10.1006/geno.1998.5380. PMID9740676.
Tinguely JN, Wermuth B (Feb 1999). "Identification of the reactive cysteine residue (Cys227) in human carbonyl reductase". European Journal of Biochemistry. 260 (1): 9–14. doi:10.1046/j.1432-1327.1999.00089.x. PMID10091578.
Finckh C, Atalla A, Nagel G, Stinner B, Maser E (Jan 2001). "Expression and NNK reducing activities of carbonyl reductase and 11beta-hydroxysteroid dehydrogenase type 1 in human lung". Chemico-Biological Interactions. 130–132 (1–3): 761–73. Bibcode:2001CBI...130..761F. doi:10.1016/S0009-2797(00)00306-9. PMID11306092.
Balcz B, Kirchner L, Cairns N, Fountoulakis M, Lubec G (2002). "Increased brain protein levels of carbonyl reductase and alcohol dehydrogenase in Down Syndrome and Alzheimer's disease". Protein Expression in Down Syndrome Brain. pp.193–201. doi:10.1007/978-3-7091-6262-0_15. ISBN978-3-211-83704-7. PMID11771743.{{cite book}}: |journal= ignored (help)
Skálová L, Nobilis M, Szotáková B, Kondrová E, Savlík M, Wsól V, Pichard-Garcia L, Maser E (Jul 2002). "Carbonyl reduction of the potential cytostatic drugs benfluron and 3,9-dimethoxybenfluron in human in vitro". Biochemical Pharmacology. 64 (2): 297–305. doi:10.1016/S0006-2952(02)01068-7. PMID12123751.
Cheon MS, Shim KS, Kim SH, Hara A, Lubec G (Jul 2003). "Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: Challenging the gene dosage effect hypothesis (Part IV)". Amino Acids. 25 (1): 41–7. doi:10.1007/s00726-003-0009-9. PMID12836057. S2CID52799223.
1wma: Crystal structure of human CBR1 in complex with Hydroxy-PP
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